1204-Head and neck SCC recurrent or metastatic cARBOplatin fluorouracil and cetuximab

Fluoropyrimidine overdose or overexposure:

Fluoropyrimidine overdose or overexposure may result in severe or life-threatening toxicity. An antidote is available and is highly effective if given within 96 hours. Read more about fluoropyrimidine overdose or overexposure.

Head and neck cancer treatment is complex and combined modality therapy is common; the involvement of a multidisciplinary team (MDT) in the initial development and ongoing evaluation of the treatment plan, and the management of the sequelae associated with treatment is recommended.

Check for clinical trials in this patient group. Link to Australian Clinical Trials website

Cycle 1

Drug	Dose	Route	Day
Cetuximab	400 mg/m²	IV infusion	1
cARBOplatin	5 AUC *	IV infusion	1
Fluorouracil	4,000 mg/m² (equivalent to 1000 mg/m²/day)	CIV	1
Cetuximab	250 mg/m²	IV infusion	8 and 15

Cycle 2 and further cycles

Drug	Dose	Route	Day
Cetuximab	250 mg/m²	IV infusion	1, 8, 15
cARBOplatin	5 AUC *	IV infusion	1
Fluorouracil	4,000 mg/m² (equivalent to 1000 mg/m²/day)	CIV	1

*if estimated GFR is 125 mL/min (i.e. AUC 5 dose > 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended

Frequency:: 21 days

Cycles:: up to 6 cycles in responding patients and consider maintenance cetuximab until disease progression or unacceptable toxicity

Drug status:

Carboplatin and fluorouracil are on the PBS general schedule

Cetuximab :TGA registered but not PBS listed for this indication

Cost:: ~ $4,740 "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic 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 antineoplastic 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

Day 1
Loratadine	10 mg (PO)	60 minutes before treatment
Dexamethasone	8 mg (PO)	60 minutes before treatment
Cetuximab	400 mg/m² (IV infusion)	over 2 hours **
Netupitant	300 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron	0.5 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with netupitant)
cARBOplatin	5 AUC (IV infusion)	in 500 mL glucose 5% over 30 to 60 minutes (if estimated GFR is 125 mL/min (i.e. AUC 5 dose > 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended)
Fluorouracil	4,000 mg/m² (CIV)	via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m²/day)

Day 2 and 3
Dexamethasone	8 mg (PO)	ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 2 and 3 may not be required and may be reduced or omitted at the clinicians discretion *

Day 8 and 15
Loratadine	10 mg (PO)	60 minutes before treatment
Dexamethasone	4 mg (PO)	60 minutes before treatment
Cetuximab	250 mg/m² (IV infusion)	over 60 minutes

Cycle 2 and further cycles

Day 1
Loratadine	10 mg (PO)	60 minutes before treatment
Dexamethasone	8 mg (PO)	60 minutes before treatment
Cetuximab	250 mg/m² (IV infusion)	over 60 minutes
Netupitant	300 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron	0.5 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with netupitant)
cARBOplatin	5 AUC (IV infusion)	in 500 mL glucose 5% over 30 to 60 minutes (if estimated GFR is 125 mL/min (i.e. AUC 5 dose > 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended)
Fluorouracil	4,000 mg/m² (CIV)	via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m²/day)

Day 2 and 3
Dexamethasone	8 mg (PO)	ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 2 and 3 may not be required and may be reduced or omitted at the clinicians discretion *

Day 8 and 15
Loratadine	10 mg (PO)	60 minutes before treatment
Dexamethasone	4 mg (PO)	60 minutes before treatment
Cetuximab	250 mg/m² (IV infusion)	over 60 minutes

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

**Although the product information recommends a maximum cetuximab infusion rate of 5 mg/min for the loading dose and 10 mg/min for subsequent doses, rates of 2 hours for the loading dose and 60 minutes for subsequent doses were used in clinical trials.^r

Frequency:: 21 days

Cycles:: up to 6 cycles in responding patients and consider maintenance cetuximab until disease progression or unacceptable toxicity

Treatment schedule - Overview

Cycle 1

Drug	Dose	Route	Day
Cetuximab	400 mg/m²	IV infusion	1
cARBOplatin	5 AUC *	IV infusion	1
Fluorouracil	4,000 mg/m² (equivalent to 1000 mg/m²/day)	CIV	1
Cetuximab	250 mg/m²	IV infusion	8 and 15

Cycle 2 and further cycles

Drug	Dose	Route	Day
Cetuximab	250 mg/m²	IV infusion	1, 8, 15
cARBOplatin	5 AUC *	IV infusion	1
Fluorouracil	4,000 mg/m² (equivalent to 1000 mg/m²/day)	CIV	1

*if estimated GFR is 125 mL/min (i.e. AUC 5 dose > 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended

Frequency:: 21 days

Cycles:: up to 6 cycles in responding patients and consider maintenance cetuximab until disease progression or unacceptable toxicity

Drug status:

Carboplatin and fluorouracil are on the PBS general schedule

Cetuximab :TGA registered but not PBS listed for this indication

Cost:: ~ $4,740 "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic 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 antineoplastic drugs are reimbursed on the PBS.

Treatment schedule - Detail

Cycle 1

Day 1
Loratadine	10 mg (PO)	60 minutes before treatment
Dexamethasone	8 mg (PO)	60 minutes before treatment
Cetuximab	400 mg/m² (IV infusion)	over 2 hours **
Netupitant	300 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron	0.5 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with netupitant)
cARBOplatin	5 AUC (IV infusion)	in 500 mL glucose 5% over 30 to 60 minutes (if estimated GFR is 125 mL/min (i.e. AUC 5 dose > 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended)
Fluorouracil	4,000 mg/m² (CIV)	via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m²/day)

Day 2 and 3
Dexamethasone	8 mg (PO)	ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 2 and 3 may not be required and may be reduced or omitted at the clinicians discretion *

Day 8 and 15
Loratadine	10 mg (PO)	60 minutes before treatment
Dexamethasone	4 mg (PO)	60 minutes before treatment
Cetuximab	250 mg/m² (IV infusion)	over 60 minutes

Cycle 2 and further cycles

Day 1
Loratadine	10 mg (PO)	60 minutes before treatment
Dexamethasone	8 mg (PO)	60 minutes before treatment
Cetuximab	250 mg/m² (IV infusion)	over 60 minutes
Netupitant	300 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron	0.5 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with netupitant)
cARBOplatin	5 AUC (IV infusion)	in 500 mL glucose 5% over 30 to 60 minutes (if estimated GFR is 125 mL/min (i.e. AUC 5 dose > 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended)
Fluorouracil	4,000 mg/m² (CIV)	via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m²/day)

Day 2 and 3
Dexamethasone	8 mg (PO)	ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 2 and 3 may not be required and may be reduced or omitted at the clinicians discretion *

Day 8 and 15
Loratadine	10 mg (PO)	60 minutes before treatment
Dexamethasone	4 mg (PO)	60 minutes before treatment
Cetuximab	250 mg/m² (IV infusion)	over 60 minutes

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

Frequency:: 21 days

Cycles:: up to 6 cycles in responding patients and consider maintenance cetuximab until disease progression or unacceptable toxicity

Indications and patient population

Recurrent or metastatic head and neck squamous cell carcinoma (SCC) in reasonably fit patients with performance status 0 to 2, who cannot tolerate cisplatin

Clinical information

Safety alert fluoropyrimidines	Fluoropyrimidines can be administered by different routes and schedules with each method having associated increased risk of certain side effects. Fluoropyrimidine overdose or overexposure is a rare but potentially life threatening side effect of this drug class and can occur by any route of administration. An antidote is available and highly effective if given within 96 hours. Read more about the medication safety alert for infusional fluorouracil and fluoropyrimidine overdose or overexposure
Venous access	Central venous access device (CVAD) is required to administer this treatment. Read more about central venous access device line selection
Hypersensitivity/infusion related reaction	High risk with cetuximab. High risk with carboplatin. Hypersensitivity risk increases with number of cycles of carboplatin.
Premedication	The product information states that premedication is required for this treatment. Please refer to the treatment schedule for suggested premedication regimen. This may be substituted to reflect institutional policy.
Emetogenicity MODERATE	Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy. Carboplatin AUC > 4 is classified by MASCC/ESMO Antiemetic Guidelines 2016 and ASCO Antiemetic Guidelines 2017 as having moderate emetogenicity. However, a NK1 receptor antagonist and a 5HT₃ receptor antagonist in combination with dexamethasone are available on the PBS for primary prophylaxis of carboplatin induced nausea and vomiting. Note: a steroid has been included both as an antiemetic and premedication for hypersensitivity in this protocol. 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
Cardiac toxicity	Cardiac toxicity is a serious complication that can occur during treatment with fluorouracil. Patients treated with fluorouracil, especially those with a prior history of cardiac disease or other risk factors, should be carefully monitored during therapy. Read more about cardiac toxicity associated with antineoplastic agents
Acneiform rash	EGFR targeted therapies are commonly associated with acneiform rash. The rash may peak in the first 2 to 4 weeks. Ensure advice on skin care (i.e. moisturisers) and sunscreen is provided. Prophylactic or early therapy with a tetracycline antibiotic (e.g. doxycycline) and 1% hydrocortisone cream to affected areas may be considered. Patients developing skin rash should be monitored for infectious sequelae, dose reductions and/or delay or cessation of treatment may be required. Read more about acneiform rash associated with EGFR inhibitors
Diarrhoea	Antidiarrhoeals (e.g. loperamide) are usually prescribed with this treatment. Read more about treatment induced diarrhoea
Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency	Rare, life-threatening toxicities such as mucositis, neutropenia, neurotoxicity and diarrhoea have been reported following administration of fluoropyrimidines (e.g. fluorouracil and capecitabine). Severe unexplained toxicities require investigation prior to continuing with treatment. Testing for DPD enzyme deficiency is available in Australia but not currently reimbursed. Read more about dihydropyrimidine dehydrogenase (DPD) enzyme deficiency
Nutrition risk HIGH	All patients should be assessed by a dietitian prior to commencement of treatment. Read more about COSA's evidence-based practice guidelines for the nutritional management of adult patients with head and neck cancer
Pulmonary toxicity	Interstitial lung disease (ILD) has been reported in patients treated with EGFR inhibitors. Read more about pulmonary toxicity associated with antineoplastic drugs.
Speech pathology	All head and neck patients presenting with either a swallowing and /or communication problem should be referred
Blood tests	FBC, EUC and LFTs at baseline and prior to each cycle. Calcium and magnesium at baseline and as clinically indicated. Recalculate carboplatin dose if significant change in weight and/or creatinine. INR as clinically indicated. Magnesium wasting syndrome is associated with this therapy and patients should be monitored for hypomagnesaemia and accompanying hypocalcaemia for up to 8 weeks after completion of treatment.
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, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.
Effects of cancer treatment on fertility	Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment. Read more about the effect of cancer treatment on fertility

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 antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note:

All dose reductions are calculated as a percentage of the starting dose.

Haematological toxicity
ANC x 10⁹/L (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.
0.5 to less than 1.0	Delay treatment until recovery
less than 0.5	Delay treatment until recovery and consider reducing carboplatin and fluorouracil by 25% for subsequent cycles
Febrile neutropenia	Delay treatment until recovery and consider reducing carboplatin and fluorouracil by 25% for subsequent cycles
Platelets x 10⁹/L (pre-treatment blood test)
75 to less than 100	The general recommendation is to delay, however if the patient is clinically well it may be appropriate to continue treatment; refer to treating team and/or local institutional guidelines.
50 to less than 75	Delay treatment until recovery
less than 50	Delay treatment until recovery and consider reducing carboplatin and fluorouracil by 25% for subsequent cycles

Renal impairment
Creatinine clearance (mL/min)
30 to 50	Reduce fluorouracil by 25% and recalculate carboplatin dose using Calvert formula
less than 30	Reduce fluorouracil by 50% and recalculate carboplatin dose using Calvert formula based on measured glomerular filtration rate (GFR) or consider omitting

Hepatic impairment
Hepatic dysfunction
Mild	No dose modifications necessary
Moderate	Reduce fluorouracil by 25%
Severe	Reduce fluorouracil by 50%

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: 1^st occurrence: No dose reduction 2^ndoccurrence: Reduce fluorouracil by 25% 3^rdoccurrence: Reduce fluorouracil by 50% 4^thoccurrence: Omit fluorouracil
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 fluorouracil by 50% 2^ndoccurrence: Omit fluorouracil

Diarrhoea
Grade 2	Delay treatment until toxicity has resolved to Grade 1 or less and reduce doses for subsequent cycles as follows: 1^st occurrence: No dose reduction 2^ndoccurrence: Reduce fluorouracil and cetuximab by 25% 3^rdoccurrence: Reduce fluorouracil and cetuximab by 50% 4^thoccurrence: Omit fluorouracil and cetuximab
Grade 3 or Grade 4	Delay treatment until toxicity has resolved to Grade 1 or less and reduce doses for subsequent cycles as follows: 1^st occurrence: Reduce fluorouracil and cetuximab by 50% 2^ndoccurrence: Omit fluorouracil and cetuximab

Hand foot syndrome (link to Hand foot syndrome (Palmar-plantar erythrodysaesthesia))
Grade 2	Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows: 1^st occurrence: No dose reduction 2^ndoccurrence: Reduce fluorouracil by 25% 3^rdoccurrence: Reduce fluorouracil by 50% 4^thoccurrence: Omit fluorouracil
Grade 3	Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows: 1^st occurrence: Reduce fluorouracil by 50% 2^ndoccurrence: Omit fluorouracil

Rash acneiform
Grade 3	Delay treatment until toxicity has resolved to Grade 2 or less and reduce the dose for subsequent cycles as follows: 1^st occurrence: No dose reduction 2^ndoccurrence: Reduce cetuximab to 200 mg/m² 3^rd occurrence: Reduce cetuximab to 150 mg/m² 4^thoccurrence: Omit cetuximab

Interactions

References & Disclaimer

Carboplatin
	Interaction	Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs)	Additive nephrotoxicity	Avoid combination or monitor renal function closely
Ototoxic drugs (e.g. aminoglycosides, frusemide, NSAIDs)	Additive ototoxicity	Avoid combination or perform regular audiometric testing
Paclitaxel	Administration schedule may influence the development of myelosuppression	Minimise toxicity by administering paclitaxel first in regimens using the combination

Cetuximab
	Interaction	Clinical management
Chemotherapeutic agents	Increased incidence of specific adverse reactions when used in combination	Monitor closely (e.g. for cardiac toxicity and hand-foot syndrome when combined with fluoropyrimidines; for severe diarrhoea with capecitabine and oxaliplatin)

Fluorouracil
	Interaction	Clinical management
Folic acid	Increased toxicity of fluorouracil due to stabilisation of its bond to thymidylate synthetase (folic acid is a precursor of folinic acid/leucovorin)	Advise patients not to take folic acid supplements (inc. multivitamins) around the time of receiving treatment with fluorouracil
Metronidazole, tinidazole	Increased toxicity of fluorouracil due to reduced clearance	Avoid combination or monitor for fluorouracil toxicity
Warfarin and other drugs metabolised by CYP2C9 (e.g. warfarin, phenytoin etc.)	Increased effect/toxicity of these drugs due to inhibition of CYP2C9 by fluorouracil resulting in reduced clearance	Avoid combination or monitor for increased effect/toxicity of these drugs (e.g. for bleeding/elevated INR with warfarin, elevated phenytoin serum levels or signs of toxicity such as ataxia, tremor etc.)

NK-1 antagonist e.g. aprepitant, fosaprepitant, netupitant
	Interaction	Clinical management
Dexamethasone	Increased effects/toxicity of dexamethasone due to inhibition of its metabolism via CYP3A4	Reduce dose of antiemetic dexamethasone by approximately 50% when adding a NK-1 antagonist. For protocols that already recommend a NK-1 antagonist, the dose reduction of antiemetic dexamethasone has already been taken into account. If dexamethasone is part of the chemotherapy protocol, dose reduction as per the product information is not routinely recommended in clinical practice and no additional dexamethasone is required for antiemetic cover.
Warfarin	Reduced anticoagulant efficacy of warfarin due to increased clearance (aprepitant induces CYP2C9). *Note interaction only applicable to aprepitant/ fosaprepitant	INR should be monitored in the 2 week period, particularly at 7 to 10 days following the administration of aprepitant/ fosaprepitant
Combined oral contraceptive	Reduced contraceptive efficacy due to increased clearance. *Note interaction only applicable to aprepitant/ fosaprepitant	Alternative non-hormonal methods should be used during and for 1 month after stopping aprepitant/ fosaprepitant
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.)	Reduced efficacy of NK-1 antagonist possible due to increased clearance	Avoid combination or monitor for decreased antiemetic effect. Consider using an alternative antiemetic regimen
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.)	Increased toxicity of NK-1 antagonist possible due to reduced clearance	Avoid combination or monitor for increased adverse effects of NK-1 antagonist (e.g. headache, hiccups, constipation)
Drugs metabolised by CYP3A4 (e.g. etoposide, imatinib, irinotecan, midazolam, paclitaxel, vinblastine, vincristine etc.)	Increased effects/toxicity of these drugs possible due to inhibition of CYP3A4 by NK-1 antagonist	Avoid combination or monitor for increased toxicity especially with orally administered drugs

General
	Interaction	Clinical management
Warfarin	Antineoplastic agents 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 antineoplastic levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).	Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. Dabigatran: avoid combination with strong P‑gp inducers and inhibitors. If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin	Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin.	Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics	Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity.	Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate. Also monitor closely for efficacy of the antineoplastic therapy.
Antiplatelet agents and NSAIDs	Increased risk of bleeding due to treatment related thrombocytopenia.	Avoid or minimise combination. If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine)	Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.)	Avoid combination. If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia). For more information link to TGA Medicines Safety Update
Vaccines	Diminished response to vaccines and increased risk of infection with live vaccines.	Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy. For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Administration

Day 1

Approximate treatment time: 3 to 4 hours

Safe handling and waste management

Safe administration

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Access port or CVC.

Pre treatment medication

Verify premedication taken or administer as prescribed.

Treatment - Time out

Cetuximab

administer via IV infusion over 2 hours (loading dose only)
if well tolerated subsequent doses over 60 minutes
although the product information recommends a maximum cetuximab infusion rate of 5 mg/min for the loading dose and 10 mg/min for subsequent doses, rates of 2 hours for the loading dose and 60 minutes for subsequent doses were used in clinical trials
observe for hypersensitivity reaction
flush with ~ 50 mL of sodium chloride 0.9%
patient should be observed for an hour post infusion. If patient has a hypersensitivity reaction – stop infusion immediately. Review by medical officer; if re-challenge indicated, pre medicate patient and recommence infusion over 2 hours, then patient should be observed for an hour post infusion.

The product information recommends waiting one hour post completion of the cetuximab infusion, before commencing concomitant chemotherapy. However, to reflect clinical practice, if no reactions are observed with the first two doses, concomitant chemotherapy may be administered immediately following cetuximab at the discretion of the treating physician.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Chemotherapy - Time out

Carboplatin

Administer carboplatin (irritant):

via IV infusion over 30 to 60 minutes
observe for hypersensitivity reactions
flush with ~100 mL of sodium chloride 0.9%
hypersensitivity risk increases with number of cycles administered.

Stop infusion at first sign of reaction:

if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate
for severe reactions seek medical assistance immediately and do not restart infusion.

Fluorouracil continuous infusion (irritant)

Connect pump containing fluorouracil and administer over the correct time for the amount of drug in the pump:

safety alert issued for administration of infusional fluorouracil
verify the correct rate of infusion via the ambulatory infusion pump
read more information about the different ambulatory infusion pumps.

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

Day 5

Approximate treatment time: 30 minutes

Safe handling and waste management

Disconnection of ambulatory infusion pump/infusor

Verify the ambulatory infusion pump/infusor is complete.

Disconnect the ambulatory infusion pump/infusor as per recommended procedure for type of pump/infusor.

Read more about ambulatory infusion pumps/infusors.

Deaccess port or CVC.

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

Day 8 and 15

Approximate treatment time: 2 hours

Handling of monoclonal antibodies and waste management

Safe administration

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Access port or CVC.

Pre treatment medication

Verify premedication taken or administer as prescribed.

Treatment - Time out

Cetuximab

administer via IV infusion
if first dose was well tolerated, administer over 60 minutes
although the product information recommends a maximum cetuximab infusion rate of 5 mg/min for the loading dose and 10 mg/min for subsequent doses, rates of 2 hours for the loading dose and 60 minutes for subsequent doses were used in clinical trials
flush with ~ 50 mL of sodium chloride 0.9%
observe for hypersensitivity reaction
If patient has a hypersensitivity reaction – stop infusion immediately. Review by medical officer; if re-challenge indicated, pre medicate patient and recommence infusion over 2 hours, then patient should be observed for an hour post infusion.

Deaccess port or CVC.

Discharge Information

Antiemetics

Antiemetics as prescribed.

Antidiarrhoeals

Antidiarrhoeals as prescribed.

Patient information

Ensure patient receives patient information sheet.

Infusion pumps

CADD-Legacy® 1 ambulatory infusion pump patient information sheet.
CADD-Legacy® Plus ambulatory infusion pump patient information sheet.
CADD® Solis VIP ambulatory infusion pump patient information sheet.
Elastomeric infusion system 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
Taste and smell alteration	Read more about taste and smell changes
Cardiotoxicity	Coronary artery spasm is a temporary, sudden narrowing of one of the coronary arteries that may present at any time during treatment with fluoropyrimidines. It most commonly manifests as angina.

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 neutropenia
Thrombocytopenia	A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding. Read more about thrombocytopenia
Oral mucositis	Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, 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
Diarrhoea	Read more about treatment induced diarrhoea
Anorexia	Loss of appetite accompanied by decreased food intake. Read more about anorexia
Fatigue	Read more about fatigue
Ocular changes	Symptoms may include eye pain, blurred vision, blepharitis, uveitis, optic neuritis, tear duct stenosis, conjunctivitis, hyperlacrimation, watery or dry eyes and photophobia.
Actinic keratoses flare	Pre-existing actinic keratoses (AKs) can become more inflamed and scaly as a result of immunosuppression. Read more about actinic keratoses flare
Acneiform rash	A skin rash, characterised by papules and pustules affecting the face and upper body. This is commonly associated with small molecule EGFR inhibitors and some monoclonal antibodies (e.g. cetuximab, panitumumab). Read more about acneiform rash associated with EGFR inhibitors
Photosensitivity	Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Hypomagnesaemia, hypokalaemia, hypocalcaemia	Abnormally low levels of magnesium, potassium and calcium in the blood.
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

Late (onset weeks to months)
Anaemia	Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. Read more about anaemia
Hyperpigmentation	Darkening of an area of skin caused by the overproduction of melanin.
Abnormal hair growth	Hair may become fine, brittle and curly. Eyelashes and eyebrows may grow more quickly and become unusually long.
Paronychia	An inflammatory reaction involving the folds of the skin surrounding the fingernail. Read about nail toxicities
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 for the use of this protocol comes from a randomised phase III trial reported by Vermorken et al.^r Between December 2004 and December 2005, 220 patients were randomised to receive cisplatin 100 mg/m² (or carboplatin AUC 5) plus fluorouracil 1000 mg/m²/day for 4 days every 3 weeks for a maximum of 6 cycles and 222 patients were randomised to receive the same chemotherapy plus weekly cetuximab at a dose of 400 mg/m² (loading dose) followed by 250 mg/m²for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxicity.

The primary end point was overall survival and secondary end points were progression-free survival, the best overall response, disease control, the time to treatment failure, the duration of the response and safety.^r

Efficacy

After a median follow up of 19.1 months in the cetuximab group and 18.2 months in the chemotherapy-alone group, the median overall survival was 10.1 months in the cetuximab group and 7.4 months in the chemotherapy-alone group (HR=0.8; 95% CI 0.64 to 0.99; p=0.04).The median progression-free survival was 5.6 months in the cetuximab group and 3.3 months in the chemotherapy-alone group (HR=0.54; 95% CI 0.43 to 0.67; p<0.001).^r

Kaplan-Meier estimates of overall survival and progression-free survival^r

Responses to treatment and survival^r

Toxicity

In general, the adverse-event profile was not affected by the addition of cetuximab with the exception of sepsis (p=0.02) and hypomagnesemia (p=0.05). Grade 3 skin reactions were seen in 9% of the patients who received cetuximab and there were six grade 3/4 infusion-related reactions among patients receiving cetuximab. 10 deaths (3 in the cetuximab group and 7 in the chemotherapy-alone group) were considered to be treatment-related.^r

Toxicity^r

References References

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History

Version 6

Date	Summary of changes
04/12/2020	Cetuximab infusion rate information in detailed treatment schedule and administration section updated to include maximum infusion rates as per product information. Version number increased to V.6.

Version 5

Date	Summary of changes
04/12/2020	Cetuximab hypersensitivity/infusion related reaction clinical information updated to include risk factors as per Medical Oncology Reference Committee meeting 23^rd October 2020. Version number increased to V.5.

Version 4

Date	Summary of changes
29/07/2011	New protocol taken to Medical Oncology Reference Committee meeting.
10/11/2011	Approved and published on eviQ.
10/04/2012	PHC OMIS view added.
11/04/2012	Post cetuximab chemotherapy waiting time changed as per discussion at Medical Oncology Reference Committee. Although the PI states waiting one hour post infusion before commencing subsequent chemotherapy, the consensus was that in clinical practice this is not necessary after the first 2 doses and should be at the discretion of the treating physician.
01/05/2012	Palonosetron added as the preferred 5HT₃ antagonist for moderate emetogenicity.
01/06/2012	PHC CVAD Pre clin added. PHC OMIS view published.
03/05/2013	Protocol Reviewed at Medical Oncology Reference Committee meeting. Next review in 2 years.
20/08/2014	PHC view removed.
09/03/2015	Carboplatin dosing - for estimated GFR > 125 mL/min, note about measuring GFR and/or dose capping added.
19/06/2015	Reviewed electronically by Medical Oncology Reference Committee. No changes. Review 2 years.
16/10/2016	Patient information sheet updated to include more fluorouracil toxicity symptom warnings.
21/10/2016	Protocol reviewed by Medical Oncology Reference Committee. No change. Review 2 years.
31/05/2017	Transferred to new eviQ website. Version number changed to V.2. Hepatitis B screening changed to NOT recommended. Antiemetic change: A NK1 receptor antagonist and a 5HT₃ receptor antagonist in combination with dexamethasone has been added as available on the PBS for primary prophylaxis of carboplatin induced nausea and vomiting.
10/05/2018	Haematological dose modifications updated as per consensus of the expert clinician group. Fluoropyrimidine overdose warning added. DPD enzyme deficiency wording in clinical information updated. Fluoropyrimidine safety alert wording in clinical information updated. Version changed to number V.3.
17/01/2019	Carboplatin AUC ≥ 4 changed from highly to moderately emetogenic as per MASCC/ESMO and ASCO guidelines and medical oncology reference committee consensus. Dexamethasone day 4 dose removed. NK1 receptor antagonist unchanged. Treatment detail and clinical information updated to reflect the change. Version number changed to V.4
15/03/2019	Protocol reviewed by Medical Oncology Reference Committee. No changes. Review 5 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:: 10 November 2011
Last reviewed:: 15 March 2019
Review due:: 30 June 2024

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/1204

14 Jun 2021

Head and neck squamous cell carcinoma recurrent or metastatic cARBOplatin fluorouracil and cetuximab

Treatment schedule Treatment schedule

Cycle 1

Cycle 2 and further cycles

Cycle 1

Cycle 2 and further cycles

Cycle 1

Cycle 2 and further cycles

Cycle 1

Cycle 2 and further cycles

Day 1

Pre treatment medication

Cetuximab

Pre treatment medication

Carboplatin

Administer carboplatin (irritant):

Stop infusion at first sign of reaction:

Fluorouracil continuous infusion (irritant)

Day 5

Disconnection of ambulatory infusion pump/infusor

Day 8 and 15

Pre treatment medication

Cetuximab

Discharge Information

Antiemetics

Antidiarrhoeals

Patient information

Infusion pumps

Efficacy

Toxicity

References References

Version 6

Version 5

Version 4