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Home , Fluorouracil, Mitomycin C

THE CLATTERBRIDGE CENTRE NHS FOUNDATION TRUST

Systemic Anti Cancer Treatment Protocol

Mitomycin C and

Chemoradiation Gynaecological Cancer

PROTOCOL REF: MPHAGMM5F (Version No: 1.2)

Approved for use in: Locally advanced carcinoma of the vulva

Dosage

Drug Dosage Route Frequency 12mg/m2 IV bolus Day 1 concurrent with (max dose 20mg) radiotherapy (5 week schedule) 5-Fluorouracil 1000mg/m2/24hours for IV Days 1 to 4 and days 29-32 (5-FU) 4 days (via 4-day concurrent with radiotherapy Baxter LV2 pump) (5 week schedule)

N.B 5FU may be administered as individual 24hr infusion bags in 1L of NaCl 0.9% over 4 days if patient needs. This requires an inpatient admission.

Supportive treatments: Domperidone 10mg oral tablets, up to 3 times a day as required Loperamide 2mg when required

Interactions – interactions with allopurinol have been observed for 5-FU; with possible decreased efficacy of 5-FU.

Anticonvulsive substances - patients taking phenytoin concomitantly should be regularly monitored for increased phenytoin plasma concentrations.

Issue Date: 14th October 2020 Review Date: October 2023 Page 1 of 7 Protocol reference: MPHAGMM5F Author: Tara Callagy Authorised by: Joanne McCaughey Version No: 1.2

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Warfarin – 5-fluorouracil can alter coagulation parameters. Monitor patients on closely. Consider changing to a low molecular weight heparin.

Folic acid – 5-fluorouracil toxicity may be enhanced.

Metronidazole – increases fluorouracil toxicity by reducing clearance

Extravasation risk Mitomycin-C: vesicant. Specific treatment available

Fluorouracil: Irritant. No specific antidote needed. Use cold compression if symptoms warrant

Administration Day Drug Dose Route Diluent and rate 1 Dexamethasone 16mg oral 30 mins before 1 Ondansetron 16mg oral 30 mins before chemotherapy 1 Mitomycin-C 12mg/m2 IV Infusion IV bolus over 10 to 15 minutes

1 to 4 5-Fluorouracil 1000mg/m2 IV Infusion IV infusion in sodium chloride 0.9% over 24 hours 29 to 32 5-Fluorouracil 1000mg/m2 IV Infusion IV infusion in sodium chloride 0.9% over 24 hours

Notes: Maximum cumulative Mitomycin dose 28mg/m2 or 56mg total

Issue Date: 14th October 2020 Review Date: October 2023 Page 2 of 7 Protocol reference: MPHAGMM5F Author: Tara Callagy Authorised by: Joanne McCaughey Version No: 1.2

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Radiotherapy  Radiotherapy will be delivered over 5 weeks on weekdays only, with concurrent chemotherapy during the first and fifth week.  Week 5 radiotherapy must be accompanied by the course of 5-fluorouracil

 5-fluorouracil must start at least 2 hours BEFORE the first fraction of radiotherapy

Main Toxicities Dihydropyrimidine dehydrogenase (DPD) deficiency DPD allows for the breakdown of 5-fluorouracil so a deficiency of this enzyme can lead to severe early 5FU toxicity. This affects approximately 3% of population and may be life threatening. DPD deficiency can be identified by the following signs/symptoms:  Early , or anaemia within a few days of 5-FU administration  Severe diarrhoea  Severe  Severe nausea and/or vomiting

Mitomycin C + 5-Florouracil Cardiac and Vascular ECG changes and pectoris-like chest pain may occur disorders with fluorouracil. Initiate standard angina investigations, refer to consultant. If symptoms persist stop fluorouracil permanently. Eye Disorders Sore eyes, conjunctivitis with 5-Fluorouracil treatment. Manage with eye drops/ointments. Gastrointestinal Nausea, vomiting, diarrhoea, constipation, mucositis and mouth ulcers. Manage with antiemetics, loperamide/codeine for diarrhoea/constipation and mouthcare for mucositis and ulcers. General disorders Pyrexia, malaise, rash, bleeding Haematological Neutropenia, anaemia, thrombocytopenia, febrile neutropenia Hepatobiliary Hepatic enzymes and blood bilirubin increased (see below)

Issue Date: 14th October 2020 Review Date: October 2023 Page 3 of 7 Protocol reference: MPHAGMM5F Author: Tara Callagy Authorised by: Joanne McCaughey Version No: 1.2

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Hypersensitivity may occur with mitomycin-C. Patients should be reactions carefully observed. If symptoms such as itching, rash, hot flush, sweating, dyspnoea and decreased blood pressure occur, treatment should be immediately discontinued and appropriate measures should be taken. Respiratory system - pulmonary oedema, interstitial pneumonia and pulmonary fibrosis, accompanied by fever, coughing, dyspnoea, abnormal x-ray findings and eosinophilia Skin disorders Alopecia, Rash, Palmar-plantar erythrodysaesthesia (PPE) Urinary system Haemolytic uremic syndrome with Mitomycin (see below)

Investigations Week Week Week Week Week Pre Comments 1 2 3 4 5 Medical Weekly whilst on X X X X X X Assessment radiotherapy SACT X X X Every administration Assessment

FBC X X X Every administration

U&E & LFT X X X This test is normally only required if a patient has not had , or fluorouracil in the past. However a consultant may still request this test if capecitabine or fluorouracil was not tolerated previously. The Dihydropyrimidine result must be available dehydrogenase before administration of X (DPD) deficiency chemotherapy unless test clear documentation from the consultant is available to the contrary. Treatment with capecitabine and fluorouracil is contraindicated in patients with known complete DPD deficiency. As per medical CT scan X management plan Informed Consent X

Issue Date: 14th October 2020 Review Date: October 2023 Page 4 of 7 Protocol reference: MPHAGMM5F Author: Tara Callagy Authorised by: Joanne McCaughey Version No: 1.2

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Repeat if clinically ECG X indicated Blood pressure Repeat if clinically X measurement indicated PS recorded X X X Every administration Toxicities X X X Every administration documented Weight recorded X X X Every administration Urine dipstick for X X Every administration protein / RBC

Dose Modifications and Toxicity Management Haematological toxicity

Proceed on day 1 if:- ANC ≥ 1.0 x 109/L Platelets ≥ 100 x 109/L

Delay 1 week on day 1 if:- ANC ≤ 0.9 x 109/L Platelets ≤ 99 x 109/L

Do not delay chemotherapy without consultant approval

 If platelets or neutrophils still below required levels for treatment at week 5, discuss with consultant. Clinical decision for individual situation.

Non-haematological toxicity Toxicity should be grading according to the CTCAE v4.0 criteria. Following assessment treatment should be withheld for any toxicity until resolved to grade 0/1. For dose modification, follow the general guidance below and discuss with treating clinician.

Grade 2 Grade 3 Grade 4 1st Interrupt treatment until Interrupt treatment until Discontinue appearance resolved to grade 0/1, resolved to grade 0/1, treatment then continue at 100% of then original dose with continue at 75-80% of prophylaxis where original dose with possible prophylaxis where possible 2nd Interrupt treatment until Interrupt treatment until appearance resolved to grade 0/1, resolved to grade0/1, then then

Issue Date: 14th October 2020 Review Date: October 2023 Page 5 of 7 Protocol reference: MPHAGMM5F Author: Tara Callagy Authorised by: Joanne McCaughey Version No: 1.2

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

continue at 75-80% of continue at 50% of original dose original dose 3rd Interrupt treatment until Discontinue treatment appearance resolved to grade 0/1, then continue at 50% of original dose 4th Discontinue treatment appearance

Haemolytic Uraemic Syndrome Mitomycin-C This is a complication of mitomycin-C. Monitor renal function / urine dipstick carefully and request red cell fragments on peripheral blood films if in doubt. It is associated with prolonged course lengths and cumulative doses above 50mg/m2 and can occur several months after treatment. Has been known at shorter and lower doses

Hepatic Impairment Mitomycin-C Mitomycin-C: dose reductions probably not necessary but discuss with consultant if AST > 2 x ULN

5-Fluorouracil

Bilirubin AST Dose (μmol/L) <85 <180 100% >85 >180 CI

Clinical decision in moderate hepatic impairment; reduce initial dose by 30%. Severe hepatic impairment, reduce initial dose by 50%

Renal Impairment Mitomycin-C Dose reduce by 25% if CrCl < 10mL/min

5-Fluorourcil Consider dose reduction if CrCl < 30mL/min

Issue Date: 14th October 2020 Review Date: October 2023 Page 6 of 7 Protocol reference: MPHAGMM5F Author: Tara Callagy Authorised by: Joanne McCaughey Version No: 1.2

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

References Summary of Product Characteristics – Mitomycin-C

Summary of Product Characteristics - Fluorouracil

Dosage Adjustment for Cytotoxics in Hepatic Impairment. January 2009 UCLH - Dosage Adjustment for Cytotoxics in Hepatic Impairment (Version 3 - updated January 2009)

Dosage Adjustment for Cytotoxics in Renal Impairment. January 2009 UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January 2009)

Stockley’s drug interactions. Ninth edition. Edited K. Baxter. Pharmaceutical press. London. 2010

Chemoradiation with 5fluorouracil and mitomycin C in the treatment of vulvar squamous cell carcinoma Gynecol Oncol 2004 93(3): 659-66

Concurrent radiation and chemotherapy in vulvar carcinoma Gynecol Oncol 1989 34(3):263-7

Concomitant 5fluorouracil, mitomycin C and radiotherapy for advanced gynecologic malignancies Int J Radiat Oncol Biol Phys 1988 15(4):901-6

Issue Date: 14th October 2020 Review Date: October 2023 Page 7 of 7 Protocol reference: MPHAGMM5F Author: Tara Callagy Authorised by: Joanne McCaughey Version No: 1.2