Haemorrhagic cystitis

The purpose of this document is to provide information to health professionals regarding the causes, symptoms and management of treatment-related haemorrhagic cystitis.

Definition

Haemorrhagic cystitis (HC) is an inflammatory process characterised by diffuse bladder mucosal inflammation with haemorrhage involving the whole bladder. Patients are at risk of developing HC following treatment with antineoplastic drugs and radiotherapy (RT). HC can occur during treatment, immediately following treatment, or the onset may be delayed for months following treatment. HC has a spectrum of manifestations and can be graded as mild, moderate or severe according to the degree of pain and amount of haematuria and/or clots. Severe cases of HC may require aggressive measures and can be associated with significant morbidity, prolonged hospitalisation and occasional mortality.^rrrr

Pathophysiology

HC is associated with the oxazaphosphorine alkylating agents cyclophosphamide and ifosfamide. These agents produce a liver metabolite called acrolein which can cause bladder damage by direct exposure and prolonged contact (dwell time) with the bladder mucosa. Incidence of HC is increased with higher individual doses, larger cumulative doses, and the use of ifosfamide as opposed to cyclophosphamide.^r

Risk factors

HC may be treatment-related, e.g.:^rrrr

• antineoplastic drugs e.g. busulfan, cabazitaxel, cyclophosphamide and ifosfamide
• intravesical therapy
• radiotherapy to the pelvic area (i.e. total dose of radiation, volume irradiated, fractionation schedule and technique)
• infection following immunosuppression and associated with allogeneic transplant e.g. BK virus, adenovirus, cytomegalovirus (CMV).^rr

Other risk factors for developing HC include:

• rate of infusion of the drug
• metabolic rate of the drug
• patient’s hydration status
• patient’s urine frequency and output
• concomitant urotoxic drugs.

Types of treatment-related haemorrhagic cystitis

Radiation-induced HC

Radiation therapy to the pelvic area can result in acute and chronic injuries to the bladder. Radiation-induced haemorrhagic cystitis (RIHC) is a rare and serious side effect for patients treated with radiation for pelvic malignancies such as prostate or cervical cancer.^r

RIHC is defined as acute or insidious diffuse vesical bleeding which occurs when the bladder vasculature undergoes tissue remodelling following damage to the bladder from radiation therapy.^rr The resulting obliterative endarteritis and poorly vascularised tissue becomes fibrotic and prone to easy damage, causing epithelial denudation, chronic ulceration, or vascular telangiectasia.^rr

RIHC can occur anywhere from 6 months to more than 10 years post radiotherapy.^rrr

Low dose chemotherapy

HC can be associated with low doses of oral and intravenous cyclophosphamide or intravenous ifosfamide.

Careful attention to the earliest symptoms of potential haemorrhagic cystitis is important to prevent progression to more severe HC.^rrrr

For patients receiving oral cyclophosphamide:^r

• administer the dose as early as possible in the day to decrease the amount of active drug metabolites remaining in the bladder overnight
• encourage patients to hydrate well and to void frequently to ensure the bladder is emptied regularly
• signs and symptoms should be treated promptly.

High dose chemotherapy

Regimens containing high doses of ifosfamide and cyclophosphamide are at risk of causing HC due to the high doses of drugs which are often infused continuously over 24 hours allowing a longer dwell time in the bladder.^r Prophylactic administration of mesna (see prevention section below) and adequate hydration may reduce the incidence of haemorrhagic cystitis.^r

Blood and marrow transplant (BMT) regimens

HC of variable severity occurs in approximately 30% of HPCT patients (mostly allogeneic). HC related to HPCT can be divided into early and late onset. They represent distinct disorders with different aetiologies and treatment implications. Treatment is dependent on the severity of the symptoms.^r

Early onset HC is generally attributable to the conditioning regimens of HPCT which often involve high doses of multiple chemotherapy drugs (e.g. busulfan, cyclophosphamide, etoposide, ifosfamide) +/- total body irradiation (TBI). Early onset HC is defined as occurring within 72 hours of the completion of conditioning. Management of early onset HC is based on a preventative approach with mesna and hyper-hydration as per high dose chemotherapy.^r

Late onset HC (day + 30 post transplant) is usually related to a viral infection with human polyomaviruses e.g. BK virus, adenovirus or cytomegalovirus (CMV). Viral mediated HC represents reactivation of a latent form of the virus in the post transplant period. Reactivation and excretion of the virus is associated with moderate to severe vesical mucosal damage with ensuing macroscopic haematuria.^rr

Signs and symptoms 

These may include:^r

• haematuria, with or without blood clots
• dysuria
• urinary frequency
• urinary urgency
• urinary incontinence
• nocturia
• suprapubic/vague abdominal discomfort and/or pain.

Investigations and diagnosis

Assess patient for the following:

• clinical assessment of bladder symptoms including:
  • the frequency and amount of urine passed
  • sense of incomplete voiding
  • poor urinary stream
  • intermittent flow
  • hesitancy
• physical examination including palpation of lower abdomen for signs of distended bladder
• medication history
• dipstick urinalysis and urine culture to exclude infection
• cystoscopy and/or urine cytology to exclude malignancy
• attend full blood count.

Grading

Over the years several grading systems have been proposed. Two commonly used systems are the CTCAE (Common Toxicity Criteria for Adverse Events) for Non-infective cystitis and the grading system developed by Droller, Saral & Santos (1982).^r

Common terminology criteria for adverse events

Common Terminology Criteria for Adverse Events 

Grading of haemorrhagic cystitis^r

Patients with any symptoms of haemorrhagic cystitis should be referred to a medical officer for management.

Prevention

The aim of prevention is to reduce the risk of damage to the bladder mucosa. Increased fluid input dilutes the concentration of acrolein while increased voiding reduces the duration of exposure.^rrrr

Some commonly used preventative measures include:^rrrrrr

• intravenous or oral hydration
• concurrent administration of mesna (see below)
• frequent voiding
• continuous bladder irrigation
• administration of diuretics such as frusemide if urine production declines (<100 mL/m²/hr)
• maintenance of urine output minimum of >100 mL/hr.

Mesna therapy

Mesna interacts with the urotoxic metabolite acrolein to reduce the incidence of cyclophosphamide and ifosfamide induced haemorrhagic cystitis. Mesna is rapidly cleared by the kidneys and does not reduce the anti-tumour effect of cyclophosphamide or ifosfamide and can be given orally or intravenously, either as a bolus injection or continuous infusion.^r

It is important that mesna is present in the bladder at the time of chemotherapy administration in order to be effective. Mesna therapy should continue for the duration of the chemotherapy and for up to 12 to 24 hours post administration. This allows for the concentration of the urotoxic metabolites to fall to non-toxic levels.^r

Various mesna dosages have been used, and harmonised dosages and methods of administration have not been established. In 2008, ASCO updated their guideline recommendations for administration of mesna with ifosfamide; note that there have been no randomised controlled trials identified since the publication of the 2002 guidelines.^r

Use of mesna with ifosfamide^r

As there are numerous mesna dose variations stated in the literature, a consensus decision was made by the eviQ Haematology Reference Committee in 2013 to have equal doses of mesna and ifosfamide on eviQ. The 1:1 ratio has been adopted from clinical practice.

Standard dose ifosfamide (< 2.5 g/m²/day) short infusion:

• daily dose of IV mesna is calculated to equal 60% of the daily ifosfamide dose, administered as three IV bolus doses to be given 15 minutes before and 4 and 8 hours after each dose of ifosfamide.

Standard dose ifosfamide (< 2.5 g/m²/day) continuous infusion:

• mesna IV bolus dose equal to 20% of the daily ifosfamide dose to be given with ifosfamide
• followed by a continuous infusion of mesna equal to 40% of the daily ifosfamide dose, during and for 12 to 24 hours after completion of ifosfamide infusion.

High dose ifosfamide (> 2.5 g/m²/day) infusion:

• there is insufficient evidence to recommend a dose of mesna
• given the longer half life of ifosfamide with higher dose therapy, more frequent and prolonged mesna dosage regimens may be necessary.

Oral mesna:^r

• the oral dose of mesna is twice the IV dose of mesna
• administration of oral mesna as an initial dose is not recommended. An IV bolus dose of mesna equal to 20% of the daily ifosfamide at the time of ifosfamide administration is recommended. Administer oral mesna 2 and 6 hours after the completion of the ifosfamide infusion, at a dose equal to 40% of the daily ifosfamide dose. The total daily dose of mesna is equal to 100% of the ifosfamide dose
• the protective effect of administering a combination of IV and oral mesna appears to be equivalent to intravenous mesna alone^r
• patients who vomit within 2 hours of taking oral mesna should repeat the dose or receive IV mesna.

Use of mesna with cyclophosphamide

Although, most centres use mesna as a prophylaxis for high-dose cyclophosphamide (doses of 50 mg/kg or 2 g/m² ) based regimens, studies have shown that this drug does not offer additional benefits if hydration and diuresis are adequate.^r The recommended daily dose for hyper-hydration is 3 L/m² in a 24 hour period. Individual patient clinical needs and preferences should be taken into account.^r

The use of hyper-hydration alone or mesna with hyper-hydration is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide.^r If used, the daily dose of mesna should be 1.0-1.5 x the daily dose of cyclophosphamide and administered intravenously.^r

Treatment

Treatment of established HC varies, is dependent on severity, and should be individualised for each patient.^r There are numerous treatment modalities reported however there is no evidence based standardised approach. Ensure you follow the health facility’s policies and procedures.

Mild HC is transient and will generally resolve with supportive treatment including hydration and pain relief.

Moderate to severe HC may require more interventional approach dependent on the severity and refractoriness of symptoms.

Prior to commencing treatment, bacterial, fungal, viral and parasitic infections need to be excluded. In the case of infection, appropriate antibacterial, antifungal, antiviral and antiparasitic agents should be administered. Late onset viral HC will require treatment of the underlying infection as well as symptom management.^r

Treatment options may include:^rrrrrr

• discontinuation of the treatment/medication
• hyper-hydration
• analgesics
• antispasmodics
• continuous bladder irrigation
• blood transfusions as required
• platelet transfusions as required.

Other measures for treatment of severe HC which have been reported in the literature include:^rrrrrrr

• surgical treatment - cystoscopy with clot evacuation and/or suprapubic catheterisation
• systemic treatment - hyperbaric oxygen (HBO)
• local treatment - intravesical therapy e.g. prostaglandins, sodium hyaluronate, growth factors, alum, oestrogen, cidofovir, sodium pentosan polysulphate, phenol, vasopressin, steroids, amifostine.

The patient and carer should have education provided where there is the risk of developing HC.^rrr

Ensure the patient is educated to:

• stay well hydrated throughout treatment
• avoid consuming bladder irritants such as alcohol and caffeine
• void regularly
• take oral cyclophosphamide in the morning (if prescribed)
• take oral mesna on time as prescribed (if prescribed)
• recognise and report the signs and symptoms of haemorrhagic cystitis including:
  • blood in their urine
  • frequency and urgency of urination
  • painful urination
  • vague abdominal pain
  • frequently waking up at night to urinate.

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Bibliography

Matz, E. L. and M. H. Hsieh. 2017. "Review of Advances in Uroprotective Agents for Cyclophosphamide- and Ifosfamide-induced Hemorrhagic Cystitis." Urology 100:16-19.

Read abstract

Cyclophosphamide and ifosfamide are widely used drugs for malignancies and rheumatologic conditions. One of the most significant adverse reactions to these drugs is hemorrhagic cystitis. Mesna is the most widely used uroprotective agent that acts to neutralize the caustic metabolite, acrolein, responsible for induction of hemorrhagic cystitis. However, mesna is not a perfect alternative, and studies since its discovery have investigated the use of alternative drugs and adjuncts to increase mesna's efficacy. This review details some of the recent work into novel uroprotective agents for drug-induced hemorrhagic cystitis.

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