2041-Oesophageal definitive ciSplatin fluorouracil chemoradiation followed by ciSplatin fluorouracil

This document is currently under review:

For queries relating to this document please contact feedback@eviq.org.au.

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.

Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency:

Testing for DPD enzyme deficiency is available in Australia but not currently reimbursed. Read more about dihydropyrimidine dehydrogenase (DPD) enzyme deficiency

This protocol is not exportable and does not have a calculator.

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

Week 1, 5, 8 and 11

Drug	Dose	Route	Day
ciSplatin	75 mg/m²	IV infusion	1
Fluorouracil	4,000 mg/m² (equivalent to 1000 mg/m²/day)	CIV via pump over 96 hours	1

Radiation therapy is usually for 5 weeks, given concurrently with the chemotherapy during week 1 and 5.

Drug status:: All drugs in this protocol are on the PBS general schedule opens in a new tab or window

Cost:: ~ $230 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.

Week 1, 5, 8 and 11

Day 1
Netupitant	300 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron	0.5 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone	12 mg (PO)	60 minutes before chemotherapy
ciSplatin	75 mg/m² (IV infusion)	in 1000 mL sodium chloride 0.9% over 60 minutes
Fluorouracil	4,000 mg/m² (CIV)	via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m²/day)

Day 2 to 4
Dexamethasone	8 mg (PO)	ONCE a day (or in divided doses) with or after food.

Radiotherapy is usually for 5 weeks, given concurrently with the chemotherapy during week 1 and 5.

Treatment schedule - Overview

Week 1, 5, 8 and 11

Drug	Dose	Route	Day
ciSplatin	75 mg/m²	IV infusion	1
Fluorouracil	4,000 mg/m² (equivalent to 1000 mg/m²/day)	CIV via pump over 96 hours	1

Radiation therapy is usually for 5 weeks, given concurrently with the chemotherapy during week 1 and 5.

Drug status:: All drugs in this protocol are on the PBS general schedule opens in a new tab or window

Cost:: ~ $230 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

Week 1, 5, 8 and 11

Day 1
Netupitant	300 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron	0.5 mg (PO)	60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone	12 mg (PO)	60 minutes before chemotherapy
ciSplatin	75 mg/m² (IV infusion)	in 1000 mL sodium chloride 0.9% over 60 minutes
Fluorouracil	4,000 mg/m² (CIV)	via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m²/day)

Day 2 to 4
Dexamethasone	8 mg (PO)	ONCE a day (or in divided doses) with or after food.

Radiotherapy is usually for 5 weeks, given concurrently with the chemotherapy during week 1 and 5.

Indications and patient population

Indications:

Definitive treatment of oesophageal cancer (squamous cell carcinoma (SCC) or adenocarcinoma) where surgery is considered inappropriate.

Cautions:

pre existing neuropathies
pre existing cardiac disease
significant hearing impairment/tinnitus.

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 opens in a new tab or window 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
Emetogenicity HIGH	Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy. Ensure that patients also have sufficient antiemetics for breakthrough emesis: Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR Prochlorperazine 10 mg PO every 6 hours when necessary. Read more about preventing anti-cancer therapy induced nausea and vomiting
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 anti-cancer drugs
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
Diarrhoea	Antidiarrhoeals (e.g. loperamide) are usually prescribed with this treatment. Read more about treatment induced diarrhoea
Cisplatin dosing	Directly measured glomerular filtration rate (mGFR) is preferred for initial dosing when eGFR < 60 mL/min/1.73 m², especially when cisplatin dose > 50 mg/m² or when eGFR is unreliable (e.g., extremes of body composition, amputees, paraplegia). Read more about prevention and management of cisplatin induced nephrotoxicity.
Hydration	Hydration helps to prevent cisplatin-induced nephrotoxicity. The default regimen is appropriate for patients with normal electrolytes, kidney function, fluid status etc. and should be adjusted according to individual requirements. Read more about cisplatin hydration regimens
Peripheral neuropathy	Assess prior to each treatment. If a patient experiences grade 2 or greater neuropathy, cessation of cisplatin is recommended; review by medical officer before commencing treatment. Read more about peripheral neuropathy Link to chemotherapy-induced peripheral neuropathy screening tool
Ototoxicity	Ototoxicity may occur with platinum-based therapy; patients should be monitored for signs and symptoms. Platinum compounds should be used with caution in patients with pre-existing conditions or risk factors. Ototoxicity may become more severe in patients being treated with other drugs with nephrotoxic potential e.g. aminoglycosides. An audiometry test should be performed if symptoms develop. Read more about ototoxicity - tinnitus and hearing loss
Growth factor support	G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk. Access the PBS website opens in a new tab or window
Blood tests	FBC, EUC, eGFR, LFTs, calcium and magnesium at baseline and prior to each treatment.
Hepatitis B screening and prophylaxis	Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy. Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations	Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. 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: All dose reductions are calculated as a percentage of the starting dose.

Haematological toxicity
ANC x 10⁹/L (pre-treatment blood test)
0.5 to less than 1.0	Delay treatment until recovery
less than 0.5	Delay treatment until recovery and consider reducing cisplatin and fluorouracil by 25% for subsequent cycles
Febrile neutropenia	Delay treatment until recovery and consider reducing cisplatin and fluorouracil by 25% for subsequent cycles
Platelets x 10⁹/L (pre-treatment blood test)
75 to less than 100	Refer to local institutional guidelines; it is the view of the expert clinicians that treatment should continue if patient is clinically well
50 to less than 75	Delay treatment until recovery
less than 50	Delay treatment until recovery and consider reducing cisplatin and fluorouracil by 25% 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)	Cisplatin	Fluorouracil
≥ 60	Full dose	Full dose
45 - 59	Consider a 25% reduction Potential for increased risk of adverse events	Full dose Increased risk of adverse events
30 - 44	AVOID Not recommended - use alternative protocol	Alternative protocol This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol
15 - 29	AVOID Not recommended - use alternative protocol	Alternative protocol This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol
< 15 (without kidney replacement therapy)	AVOID Not recommended - use alternative protocol	AVOID Not recommended - use alternative protocol

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

Peripheral neuropathy
Grade 2 , Grade 3 or Grade 4	Omit cisplatin

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 the dose for subsequent cycles as follows: 1^st occurrence: No dose reduction 2^ndoccurrence: Reduce fluorouracil 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

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 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

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 (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.

Cisplatin
	Interaction	Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs)	Additive nephrotoxicity	Avoid combination or monitor kidney function closely
Ototoxic drugs (e.g. aminoglycosides, frusemide, NSAIDs)	Additive ototoxicity	Avoid combination or perform regular audiometric testing
Neurotoxic drugs (e.g. vincristine, paclitaxel)	Additive neurotoxicity	Monitor closely for neuropathy if combination used
Paclitaxel	Administration schedule may influence the development of myelosuppression	Minimise toxicity by administering paclitaxel first in regimens using the combination
Carbamazepine, phenytoin, valproate	Decreased antiepileptic plasma levels	Monitor antiepileptic serum levels and seizure frequency for efficacy; adjust dosage as appropriate or select alternative antiepileptic (e.g. clonazepam, diazepam, lorazepam)

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.)
Allopurinol	Reduced efficacy of fluorouracil possible due to reduced conversion to the active metabolites	Avoid combination or monitor for reduced fluorouracil efficacy

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

General
	Interaction	Clinical management
Warfarin	Anti-cancer drugs may alter the anticoagulant effect of warfarin.	Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran	Interaction with both CYP3A4 and P-gp inhibitors /inducers. DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).	Apixaban: avoid concurrent use with strong CYP3A4 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: 4 hours

Safe handling and waste management

Safe administration

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.

Anti-cancer drug induced neuropathy screening tool prior to each treatment.

Prime IV line(s).

Access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Verify dexamethasone taken or administer as prescribed.

Chemotherapy - Time out

Cisplatin

Commence prehydration for cisplatin:

administer 10 mmol magnesium sulphate (MgSO₄) in 1000 mL sodium chloride 0.9% over 60 minutes
ensure patient has passed urine prior to cisplatin administration as per institutional policy.

Administer cisplatin (irritant):

via IV infusion over 60 minutes
flush with 100 mL of sodium chloride 0.9%
observe for hypersensitivity reactions which can increase with the number of cycles administered and when given with concomitant radiation therapy.

Infusion-related reaction (IRR):

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

Post hydration:

1000 mL sodium chloride 0.9% over 60 minutes.

Fluorouracil continuous infusion (irritant)

Safety alert fluoropyrimidines

Administer fluorouracil:

connect ambulatory infusion pump containing fluorouracil to TIVAD or CVAD
verify the correct rate of infusion as per the treatment schedule
read more 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 TIVAD or CVAD.

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

Discharge information

Antiemetics - as/if prescribed.

Antidiarrhoeals - as/if prescribed.

Patient information

Ensure patient receives protocol patient information sheet.

Infusion pumps 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)
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 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
Oral mucositis	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
Diarrhoea	Read more about treatment induced diarrhoea
Anorexia	Loss of appetite accompanied by decreased food intake. Read more about anorexia
Ocular changes	Symptoms may include eye pain, blurred vision, blepharitis, uveitis, optic neuritis, tear duct stenosis, conjunctivitis, hyperlacrimation, watery or dry eyes and photophobia.
Fatigue	Read more about fatigue
Peripheral neuropathy	Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet. It is associated with several classes of anti-cancer drugs. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma. Read more about peripheral neuropathy
Ototoxicity	Tinnitus and hearing loss may occur due to damage in the inner ear. Tinnitus is usually reversible, while hearing loss is generally irreversible. Hearing loss is dose-related, cumulative and may be worse in those with pre-existing hearing problems. Read more about ototoxicity - tinnitus and hearing loss
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
Photosensitivity	Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Nephrotoxicity	Kidney dysfunction resulting from damage to the glomeruli, tubules or renal vasculature.
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.
Nail changes	Hyperpigmentation, paronychia, onycholysis, splinter haemorrhage, pyogenic granuloma formation, subungual haematoma and subungual hyperkeratosis are some of the nail changes associated with anti-cancer drugs. Read more about nail toxicities

Evidence

The evidence supporting this protocol is provided by a phase III intergroup randomised trial (RTOG 85-01) involving 123 patients, comparing chemoradiation therapy versus radiation therapy alone in patients with localised oesophageal cancer.^r ^r 62 patients were randomised to receive radiation therapy alone (64 Gy over 6.4 weeks) and 61 patients were randomised to receive 4 cycles of cisplatin and fluorouracil with radiation therapy (50 Gy) delivered during the first 5 weeks.^r ^r Cisplatin 75 mg/m² was administered on day 1 of weeks 1, 5, 8 and 11, and fluorouracil 1000 mg/m² per day was administered on day 1 to 4 of weeks 1, 5, 8 and 11. The primary end point was overall survival and secondary endpoints were patterns of treatment failure and toxicities.

Although small numbers (62 patients), the dramatic survival differences at 5 years has led to the adoption of this study and continuing use of this regimen 25 years after study publication.

Efficacy

In the RTOG 85-01 trial, combined therapy (chemoradiation therapy) significantly increased overall survival compared to radiation therapy alone. At 5 years of follow-up the overall survival for chemoradiation therapy was 26% (95% CI, 15%-37%) compared with 0% for radiation therapy alone. Persistence of disease was less common in the chemoradiation therapy group (26%) than in the radiation therapy alone group (37%).^r

There is some uncertainty over whether SCC has a higher response than adenocarcinoma.

Toxicity

In the RTOG 85-01 trial grade 4 toxicities were greater in the chemoradiation therapy group compared with the radiation therapy alone group. Grade 4 toxicities were reported in 8% of patients in the chemoradiation therapy group, compared with 2% in the radiation alone group.^r ^r 1 patient in the chemoradiation therapy group died from renal and bone marrow failure. There were no significant differences in severe late toxicities between the two groups.^r ^r

References References

[%id%]: [%title%]

Read abstract

[%abstract%]
: Conroy, T., M. P. Galais, J. L. Raoul, et al. 2014. "Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial." Lancet Oncol 15(3):305-314.

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BACKGROUND: Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer. METHODS: We did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I-IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0-2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), bolus fluorouracil 400 mg/m(2), and infusional fluorouracil 1600 mg/m(2) (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m(2) per day for 4 days and cisplatin 75 mg/m(2) on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00861094. FINDINGS: 134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25.3 months (IQR 15.9-36.4). Median progression-free survival was 9.7 months (95% CI 8.1-14.5) in the FOLFOX group and 9.4 months (8.1-10.6) in the fluorouracil and cisplatin group (HR 0.93, 95% CI 0.70-1.24; p=0.64). One toxic death occurred in the FOLFOX group and six in the fluorouracil-cisplatin group (p=0.066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 [47%] events in 131 patients in the FOLFOX group vs three [2%] in 128 patients in the cisplatin-fluorouracil group, p < 0.0001), sensory neuropathy (24 [18%] vs one [1%], p < 0.0001), increases in aspartate aminotransferase concentrations (14 [11%] vs two [2%], p=0.002), and increases in alanine aminotransferase concentrations (11 [8%] vs two [2%], p=0.012) were more common in the FOLFOX group, whereas serum creatinine increases (four [3%] vs 15 [12%], p=0.007), mucositis (35 [27%] vs 41 [32%], p=0.011), and alopecia (two [2%] vs 12 [9%], p=0.005) were more common in the fluorouracil and cisplatin group. INTERPRETATION: Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery. FUNDING: UNICANCER, French Health Ministry, Sanofi-Aventis, and National League Against Cancer.
: Minsky, B. D., T. F. Pajak, R. J. Ginsberg, et al. 2002. "INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy." J.Clin Oncol 20(5):1167-1174.

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PURPOSE: To compare the local/regional control, survival, and toxicity of combined-modality therapy using high-dose (64.8 Gy) versus standard-dose (50.4 Gy) radiation therapy for the treatment of patients with esophageal cancer. PATIENTS AND METHODS: A total of 236 patients with clinical stage T1 to T4, N0/1, M0 squamous cell carcinoma or adenocarcinoma selected for a nonsurgical approach, after stratification by weight loss, primary tumor size, and histology, were randomized to receive combined-modality therapy consisting of four monthly cycles of fluorouracil (5-FU) (1,000 mg/m(2)/24 hours for 4 days) and cisplatin (75 mg/m(2) bolus day 1) with concurrent 64.8 Gy versus the same chemotherapy schedule but with concurrent 50.4 Gy. The trial was stopped after an interim analysis. The median follow-up was 16.4 months for all patients and 29.5 months for patients still alive. RESULTS: For the 218 eligible patients, there was no significant difference in median survival (13.0 v 18.1 months), 2-year survival (31% v 40%), or local/regional failure and local/regional persistence of disease (56% v 52%) between the high-dose and standard-dose arms. Although 11 treatment-related deaths occurred in the high-dose arm compared with two in the standard-dose arm, seven of the 11 deaths occurred in patients who had received 50.4 Gy or less. CONCLUSION: The higher radiation dose did not increase survival or local/regional control. Although there was a higher treatment-related mortality rate in the patients assigned to the high-dose radiation arm, it did not seem to be related to the higher radiation dose. The standard radiation dose for patients treated with concurrent 5-FU and cisplatin chemotherapy is 50.4 Gy

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History

Version 5

Date	Summary of changes
07/09/2023	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.5.

Date

Summary of changes

07/09/2023

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.5.

Version 4

Date	Summary of changes
08/10/2019	Clinical information updated with PBS expanded indications for GCSF.

Version 3

Date	Summary of changes
28/06/2017	New protocol developed. Based on ID: 328 Oesophageal Definitive ciSplatin (Fractionated) and Fluorouracil Chemoradiation, see history tab of ID: 328 for all previous changes to the protocol. Reviewed electronically by Medical Oncology Reference Committee and published on eviQ.
16/02/2018	Fluoropyrimidine overdose or overexposure warning added.
10/05/2018	Haematological dose modifications updated as per consensus of the expert clinician group. DPD enzyme deficiency wording in clinical information updated. Fluoropyrimidine safety alert wording in clinical information updated. Version number changed to V.3.
20/05/2019	Protocol reviewed electronically by the 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:: 28 June 2017
Last reviewed:: 20 May 2019
Review due:: 30 June 2024

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01 May 2025

Oesophageal definitive ciSplatin and fluorouracil chemoradiation followed by ciSplatin and fluorouracil

Treatment schedule - Overview

Week 1, 5, 8 and 11

Treatment schedule - Detail

Week 1, 5, 8 and 11

Indications and patient population

Indications:

Cautions:

Clinical information

Dose modifications

Interactions

Administration

Day 1

Pre treatment medication

Chemotherapy - Time out

Cisplatin

Commence prehydration for cisplatin:

Administer cisplatin (irritant):

Infusion-related reaction (IRR):

Post hydration:

Fluorouracil continuous infusion (irritant)

Administer fluorouracil:

Day 5

Disconnection of ambulatory infusion pump/infusor

Discharge information

Patient information

Side effects

Evidence

Efficacy

Toxicity

References References

Bibliography

Literature search

History

Version 5

Version 4

Version 3