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Anal definitive mitomycin and fluorouracil chemoradiation

This protocol was published over 10 years ago and has been assessed by the reference committee as suitable to be reviewed as required. The review due date has been removed. If something in this protocol requires reference committee consideration, please click on the feedback button at the bottom of the page.

Read more about the as required review process in this factsheet.

 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.

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

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Drug Dose Route Day
Mitomycin 12 mg/m2 (Cap dose at 20 mg) IV 1 *
Fluorouracil 4,000 mg/m2 (equivalent to 1000 mg/m2/day) CIV via pump over 96 hours 1 and 29

*It is the consensus of the Reference Committee to follow the ACT II trial which administered Mitomycin C on Day 1 only at a dose of 12 mg/m2.r

Cycles:
1 with concurrent radiation therapy
Notes:

Both Radiation oncologists and Medical oncologists need to be involved in decisions regarding treatment delays or dose alterations.

Mitomycin/5-FU remains the standard of care for anal cancer, however, the use of cisplatin/5-FU is also a reasonable approach in some patients in whom the toxicity of mitomycin would be considered unacceptable or where mitomycin is contraindicated such as idiosyncratic or hypersensitivity reactions, coagulation and bleeding disorders and thrombocytopenia (platelets less than 100 x 109/L).

As the majority of clinical trials have excluded patients with HIV/AIDS, information is limited on how to treat such patients. Prior to the HAART (highly active antiretroviral therapy) era, patients with HIV/AIDS were reported to have reduced survival and significant acute toxicities to standard chemoradiation therapy. Since the introduction of HAART, there has been evidence to suggest that chemoradiation therapy with mitomycin/5-FU may be safe and effective in this patient population.rr However, other factors such as performance status, CD4 count, compliance with HAART, HIV/AIDS-related complications (e.g. opportunistic infections etc.) need to be taken into consideration when determining a treatment regimen and/or dose adjustments.

Drug status:

Mitomycin is TGA registered but not PBS listed

Fluorouracil is on the PBS general schedule

Cost:
~ $290 per cycle, excluding mitomycin "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, 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.

Day 1
Metoclopramide 10 mg (PO)

one tablet when necessary (maximum of 30 mg/24 hours, up to 5 days)
Mitomycin 12 mg/m2 (IV) (Cap dose at 20 mg) over 15 minutes
Fluorouracil 4,000 mg/m2 (CIV) via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m2/day)
Day 29
Metoclopramide 10 mg (PO)

one tablet when necessary (maximum of 30 mg/24 hours, up to 5 days)
Fluorouracil 4,000 mg/m2 (CIV) via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m2/day)

*It is the consensus of the Reference Committee to follow the ACT II trial which administered Mitomycin C on Day 1 only at a dose of 12 mg/m2.r

Cycles:
1 with concurrent radiation therapy
Drug Dose Route Day
Mitomycin 12 mg/m2 (Cap dose at 20 mg) IV 1 *
Fluorouracil 4,000 mg/m2 (equivalent to 1000 mg/m2/day) CIV via pump over 96 hours 1 and 29

*It is the consensus of the Reference Committee to follow the ACT II trial which administered Mitomycin C on Day 1 only at a dose of 12 mg/m2.r

Cycles:
1 with concurrent radiation therapy
Notes:

Both Radiation oncologists and Medical oncologists need to be involved in decisions regarding treatment delays or dose alterations.

Mitomycin/5-FU remains the standard of care for anal cancer, however, the use of cisplatin/5-FU is also a reasonable approach in some patients in whom the toxicity of mitomycin would be considered unacceptable or where mitomycin is contraindicated such as idiosyncratic or hypersensitivity reactions, coagulation and bleeding disorders and thrombocytopenia (platelets less than 100 x 109/L).

As the majority of clinical trials have excluded patients with HIV/AIDS, information is limited on how to treat such patients. Prior to the HAART (highly active antiretroviral therapy) era, patients with HIV/AIDS were reported to have reduced survival and significant acute toxicities to standard chemoradiation therapy. Since the introduction of HAART, there has been evidence to suggest that chemoradiation therapy with mitomycin/5-FU may be safe and effective in this patient population.rr However, other factors such as performance status, CD4 count, compliance with HAART, HIV/AIDS-related complications (e.g. opportunistic infections etc.) need to be taken into consideration when determining a treatment regimen and/or dose adjustments.

Drug status:

Mitomycin is TGA registered but not PBS listed

Fluorouracil is on the PBS general schedule

Cost:
~ $290 per cycle, excluding mitomycin "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, 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.

Day 1
Metoclopramide 10 mg (PO)

one tablet when necessary (maximum of 30 mg/24 hours, up to 5 days)
Mitomycin 12 mg/m2 (IV) (Cap dose at 20 mg) over 15 minutes
Fluorouracil 4,000 mg/m2 (CIV) via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m2/day)
Day 29
Metoclopramide 10 mg (PO)

one tablet when necessary (maximum of 30 mg/24 hours, up to 5 days)
Fluorouracil 4,000 mg/m2 (CIV) via ambulatory infusion pump over 96 hours (equivalent to 1000 mg/m2/day)

*It is the consensus of the Reference Committee to follow the ACT II trial which administered Mitomycin C on Day 1 only at a dose of 12 mg/m2.r

Cycles:
1 with concurrent radiation therapy
  • Primary treatment of anal cancer.
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
Emetogenicity LOW

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
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
Blood tests

FBC, EUC, eGFR and LFTs at baseline and prior to each treament. Monitor FBC for 6 to 8 weeks after last dose of mitomycin due to prolonged period of myelosuppression associated with mitomycin.
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.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.

Read more about COVID-19 vaccines and cancer.
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 foetal 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
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) 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 fluorouracil by 25% for subsequent cycles
Febrile neutropenia Delay treatment until recovery and consider reducing 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 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)		 Fluorouracil Mitomycin
≥ 60

Full dose

Full dose
45 - 59

Full dose

Increased risk of adverse events

Full dose

Potential for increased risk of adverse events
30 - 44

Full dose

Increased risk of adverse events

Full dose

Potential for increased risk of adverse events
15 - 29

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol

AVOID

Not recommended - use alternative 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%
Mucositis and stomatitis
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less
Grade 3 or Grade 4 Delay treatment until toxicity has resolved to Grade 1 or less and reduce fluorouracil by 50% for subsequent cycles
Diarrhoea
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less
Grade 3 or Grade 4 Delay treatment until toxicity has resolved to Grade 1 or less and reduce fluorouracil by 50% for subsequent cycles
Hand foot syndrome  (link to Hand foot syndrome (Palmar-plantar erythrodysaesthesia)
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less
Grade 3 Delay treatment until toxicity has resolved to Grade 1 or less and reduce fluorouracil by 50% for subsequent cycles

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources: 

For more information see References & Disclaimer.

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
Mitomycin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Tamoxifen Increased risk of mitomycin induced haemolytic uraemic syndrome Monitor for signs of haemolytic uraemic syndrome (e.g. renal failure, thrombocytopenia, microangiopathic anaemia, hypertension etc.)
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 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 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
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

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. 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 and Australian Injectable Drugs Handbook websites for further information.

Day 1

Approximate treatment time: 30 minutes

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

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

Prime IV line(s).

Access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Mitomycin

Extravasation of a vesicant is a medical emergency. Monitor for signs of extravasation throughout administration.

Administer mitomycin (vesicant):
  • over 15 minutes
    • via a minibag 
      OR
    • by IV bolus via a side port of a freely flowing IV infusion
  • flush with ~150 mL of sodium chloride 0.9%.

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 TIVAD or CVAD.

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

Day 29

Approximate treatment time: 30 minutes

Prime IV line(s).

Access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

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 33

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.

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.
Extravasation, tissue or vein injury

The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue.

Read more about extravasation management

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
Diarrhoea

Read more about treatment induced diarrhoea
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
Ocular changes

Symptoms may include eye pain, blurred vision, blepharitis, uveitis, optic neuritis, tear duct stenosis, conjunctivitis, hyperlacrimation, watery or dry eyes and photophobia. 
Oesophagitis

Inflammation of the mucosal lining of the oesophagus.  It can progress to ulceration, haemorrhage, secondary infection and pain.
Fatigue

Read more about fatigue
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.
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
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
Haemolytic uraemic syndrome (HUS)

A rare but serious acute syndrome characterised by haemolysis of red blood cells and kidney failure.

Read more about haemolytic uraemic syndrome (HUS)

Early studies have demonstrated that adding mitomycin to 5-FU results in improved local control and disease free survival in patients with anal cancer. All studies have shown that mitomycin adds significantly to toxicity.r, r, r

A large prospective randomised trial, RTOG 98-11,r compared mitomycin/5-FU in combination with radiation therapy, directly to cisplatin/5-FU in combination with radiation therapy. 682 patients with anal canal carcinoma were randomised to either mitomycin 10 mg/m2 Day 1 and Day 29 combined with infusional 5-FU 1000 mg/m2/day Day 1 to 4 or cisplatin 75 mg/m2 Day 1, Day 29, Day 57 and Day 85 combined with infusional 5-FU 1000 mg/m2/day Day 1 to 4, Day 29 to 32, Day 57 to 60 and Day 85 and 89. Both regimens were given radiation therapy at a minimum dose of 45 Gy in 25 fractions. Patients with established AIDS were excluded.r​

ACT II,r a large randomised multicentre trial investigated the role of replacing mitomycin with cisplatin in improving responses with acceptable toxicity and whether maintenance treatment after chemoradiation improves survival. Between June 4, 2001, and Dec 16, 2008, 940 patients with histologically proven anal squamous, basaloid or cloacogenic carcinoma were equally randomised in a 2x2 factorial design to receive 5-FU 1000 mg/m2/day days 1 to 4 and days 29 to 32 and either mitomycin 12 mg/m2 day 1 or cisplatin 60 mg/m2 day 1 and day 29. Radiation therapy of 50.4 Gy was delivered in 28 daily fractions over 5.5 weeks with a two-phase technique. 4 weeks after chemoradiation, patients were also randomised to receive maintenance therapy (2 cycles of cisplatin and 5-FU weeks 11 and 14) or no maintenance.

Efficacy

RTOG 98-11r

The median follow-up for all patients was 2.51 years. Although the 5 year disease survival rate and overall survival rate were similar between both arms, the cumulative colostomy rate was significantly higher in the cisplatin/5-FU arm.r

Ajanir Mitomycin/5FU  Cisplatin/5FU p-value
5 year disease free survival rate 60% 54% 0.17
5 year overall survival rate 75% 70% 0.10
5 year loco-regional survival rate 25% 33% NR
5 year distant metastasis rate 15% 19% NR
Cumulative colostomy rate 10% 19% 0.02

NR: not reported

© Journal of American Medical Association 2008

ACT IIr

The median follow-up was 5.1 years. 77% mitomycin group (365/472) and 72% cisplatin group (338/468) completed chemoradiation without delays or dose reductions. 46% mitomycin group (105/226) and 41% cisplatin group (91/222) completed both courses of maintenance treatment without delays or dose reductions. There were no significant differences in the complete responses (absolute difference -0.9%, 95% CI -4.9 to 3.1; p=0.64) between the mitomycin and the cisplatin arms. Progression-free survival did not differ significantly between patients who took mitomycin and cisplatin during chemoradiation (HR 0.95, 95% CI 0.75–1.19; p=0.63). The addition of maintenance treatment did not improve the 3 year PFS. The 3 year PFS was better in patients with T1-T2 and node negative patients in comparison with T3-T4 and node positive patients. There was no significant difference in the 3 year OS between mitomycin and cisplatin arms and the maintenance and no maintenance arms.

Primary tumour response at 26 weeksr Mitomycin group
(n=432)		 Cisplatin group
(n=431)
Complete response 391 (90.5%) 386 (89.6%)
Partial response 14 (3.2%) 24 (5.6%)
Stable disease 5 (1.2%) 6 (1.4%)
Progressive disease 22 (5.1%) 15 (3.5%)
Efficacyr Mitomycin
maintenance		 Cisplatin
maintenance		 Mitomycin,
no maintenance		 Cisplatin,
no maintenance
3 year PFS 73%
95% CI (66-78) 		 74%
95% CI (68-80) 		 73%
95% CI (67-78)		 72% 
95% CI (66-78) 
3 year colostomy free survival 73%
95% CI (67-79)		 75%
95% CI (68-80)		 75%
95% CI (68-80)		 72%
95% CI (66-77)
3 year OS 82% 83%  86% 84%

Progression-free survival (A) maintenance vs non maintenance (B) all four groupsr

© Lancet Oncology 2013

Anal cancer mortality (A) Cisplatin vs mitomycin (B) all four groupsr


© Lancet Oncology 2013

© Lancet Oncology 2013

Toxicity

RTOG 98-11r

The rate of acute non haematologic grade 3 or 4 toxicity was 74% in both the mitomycin- and cisplatin-based groups. A post hoc analysis of severe grade 3/4 acute haematologic toxicity showed a significantly greater incidence in the mitomycin-based group (61%) compared to the cisplatin-based group; (42%) (p=0.001).

© Journal of the American Medical Association 2008

ACT IIr

Patients in the mitomycin arm had more acute grade 3/4 haematological toxicities (26% versus 16%; p< 0.001) but no higher rates of febrile neutropenia (3.1% versus 3.2%; p=0.93). Non-haematologic grade 3/4 toxicities were similar between arms (61% versus 65%; p=0.22).

© Lancet Oncology 2013

Earlier studies

Non-haematological toxicities of the gastrointestinal tract, skin and mucous membranes occur with equal frequency in patients treated with mitomycin C/5-FU vs 5-FU alone. The risk of neutropenic sepsis and thrombocytopenia, however, is significantly increased by the addition of mitomycin. In Flam et al.,r 23% of patients on mitomycin/5-FU experienced grade 4 toxicity and 2.7% experienced fatal toxicity. All patients who died toxic deaths had neutropenic sepsis.

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Version 7

Date Summary of changes
31/01/2024 Protocol assessed by eviQ medical oncology reference committee and deemed suitable to be reviewed as required. Flag added, review date removed and version number increased to V.7. Read more about as required review protocol status in this factsheet.

Version 6

Date Summary of changes
14/09/2023

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.6.
11/01/2024 Drug cost updated to exclude mitomycin

Version 5

Date Summary of changes
08/10/2019 Clinical information updated with PBS expanded indications for GCSF.
25/09/2020 Protocol reviewed electronically by the Medical Oncology Reference committee. No changes. Next review in 2 years.
20/10/2022 Protocol reviewed electronically by Medical Oncology Reference Committee. No changes. Next review 4 years.

Version 4

Date Summary of changes
09/02/2007 Fluorouracil maximum dose of 2000 mg /day added
04/05/2007 Mitomycin maximum dose of 20 mg added
03/12/2007 Bowel wall injury information and safety alert added
03/03/2010 Mitomycin dose changed to 12 mg/m2 (was previously 10 mg/m2) as per ACT II trial. Statement on treating patients with HIV included. Evidence updated, new dose modifications and transferred to eviQ.
28/11/2011

New format to allow for export of protocol information.
Protocol version number changed to V.2.
Title updated to include "definitive". "with radiotherapy changed to "chemoradiation".
Emetogenicity changed to low (was moderate).
Antiemetics and premedications added to the treatment schedule.
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations.
Drug specific information placed behind the drug name link.
Treatment schedule changed from two cycles every 28 days to one cycle day 1 and 29.
04/04/2012 PHC OMIS view updated
13/09/2013 Protocol reviewed at Medical Oncology Reference Committee.
Evidence updated with James Lan Onc 2013.
Next review in 2 years.
08/09/2014 PHC view removed
18/09/2015 Link to radiation oncology protocol added
18/02/2016 Discussion with Medical Oncology Reference Committee Chairs and protocol to be reviewed every 5 years. Next review due in 3 years.
16/10/2016 Patient information sheet updated to include more fluorouracil toxicity symptom warnings.
09/11/2016 The following change made post Medical Oncology Reference Committee meeting held on 21 October 2016: link to AGTIG and ANZCTR added.
04/05/2017 Discussion with Medical Oncology Reference Committee regarding fluorouracil dose, and 'maximum dose of 2000 mg/day' for fluorouracil removed from treatment schedule as no longer appropriate.
31/05/2017

Transferred to new eviQ website. Version number change to V.3.
16/02/2018 Protocol reviewed electronically by Medical Oncology Reference Committee. Fluoropyrimidine warning added. Review in 5 years.
19/2/2018 Note added below treatment schedule stating protocol follows ACT II trial for the Mitomycin C dosing.
10/05/2018 Haematological dose modifications updated as per consensus of the expert clinician group. Fluorouracil toxicity profile in clinical information removed. Version number changed to V.4.

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11 Oct 2024