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 resulting in haemorrhage. Patients are at risk of developing HC following blood and marrow transplant (BMT) or treatment with anti-cancer and supportive therapies or radiation therapy (RT). Onset of HC can occur during or immediately following treatment or may be delayed for months to years following treatment. Severe cases of HC may require aggressive measures and can be associated with significant morbidity, prolonged hospitalisation and occasional mortality.^rrrr

Pathophysiology

HC is most commonly associated with the oxazaphosphorine alkylating agents cyclophosphamide and ifosfamide. The liver metabolises these agents to acrolein which is excreted by the kidneys. Prolonged contact (dwell time) of acrolein with the bladder mucosa causes a pyroptotic reaction in the bladder urothelium, leading to HC.^r The frequency of patients developing HC is 20 – 25% in the weeks or months after cyclophosphamide chemotherapy.^r The incidence is increased with higher individual doses and larger cumulative doses of anti-cancer drugs.^r

RT to the pelvic area can result in acute and chronic injuries to the bladder including radiation-induced HC. Radiation-induced HC is defined as sudden or gradually worsening diffuse vesical bleeding.^rr Early-onset RT injuries to the bladder are generally associated with damage to the rapidly dividing cells of the bladder mucosa which can cause inflammation and tissue oedema (swelling).^r Late-onset bladder injury resulting in HC follows the progressive obliteration of the small blood vessels of the bladder mucosa (obliterative endarteritis) with consequent development of hypoxia and tissue damage. The tissue becomes atrophied, fibrotic and prone to easy damage, causing epithelial denudation, chronic ulceration, or vascular telangiectasia.^rr This progressive deterioration can result in necrosis of tissue reliant on those vessels and, subsequently, haematuria.^r

Risk factors

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

• anti-cancer therapies and related supportive treatments, e.g., busulfan, cabazitaxel, antithymocyte globulin (ATG), cyclophosphamide and ifosfamide
• intravesical therapy
• radiation therapy 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
• blood and marrow transplant (BMT) donor-recipient gender mismatches (early-onset)
• bone marrow as a source of stem cells (late-onset)
• systemic disease, i.e. amyloidosis.^rr

Types of treatment-related haemorrhagic cystitis

Radiation-induced HC

Radiation-induced HC is a rare and serious side effect for patients treated with pelvic RT.^r Chronic radiation-induced cystitis occurs in approximately 5-10% of pelvic RT patients, with severe haematuria occurring 5-8% of the time.^r Onset of symptoms is on average 31.8 months after completing radiation therapy but can occur anywhere from 6 months to more than 10 years post-radiation therapy.^rrrr It also more commonly occurs in males than females (2.8:1).^r The reported onset and incidence vary in the literature due to differences in tumour type and extent, treatment technique and type of radiation used, and prescribed radiation dose (fractionation and total dose).^r

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 essential 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 often infused continuously over 24 hours, allowing a longer dwell time in the bladder.^r Prophylactic administration of mesna (see management section below) and adequate hydration may reduce the incidence of haemorrhagic cystitis.^r

Blood and marrow transplant (BMT)

HC of variable severity occurs in approximately 30% of BMT patients (mostly allogeneic). HC related to BMT 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 BMT, which often involve high doses of anti-cancer therapies and related supportive treatments (e.g. busulfan, cyclophosphamide, etoposide, ifosfamide, ATG) +/- 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 hyperhydration 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, micro- to macroscopic, +/- blood clots
• dysuria
• urinary frequency
• urinary urgency
• urinary incontinence
• pollakiuria
• 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 and post-void bladder scan
• medication history
• dipstick urinalysis and urine culture to exclude infection
• cystoscopy and/or urine cytology to exclude malignancy
• attend full blood count.

Grading

When grading HC, the most commonly used grading systems are the CTCAE (Common Toxicity Criteria for Adverse Events) (Table 1) for non-infective cystitis and the grading system developed by Droller, Saral & Santos (Table 2).^r

Table 1: Common terminology criteria for adverse events

Common Terminology Criteria for Adverse Events 

Table 2: Grading of haemorrhagic cystitis^r

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

Prevention

Prevention aims 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
• hyperhydration
• concurrent administration of mesna (see below)
• frequent voiding, encourage to void at the first sensation
• encouraging voiding from a standing or sitting postilion rather than in a recumbent position as the posterior wall of the bladder is often involved in HC
• administration of diuretics such as frusemide if urine production declines (< 100 mL/m²/hr)
• maintenance of urine output minimum of > 100 mL/hr.

There are no clear guidelines for the prevention of radiation-induced HC. ^rr

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. It can be given orally or intravenously, either as a bolus injection or continuous infusion.^r

Mesna must be 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 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 2002 guidelines.^r

Treatment

Treatment of established HC varies depending on the 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 your facility’s policies and procedures.

Mild HC is transient and generally resolves with supportive treatment, including hydration, anticholinergic bladder medications and pain relief.

Moderate to severe HC may require more active intervention, dependent on the severity and refractoriness of symptoms.

Before commencing treatment, bacterial, fungal, viral and parasitic infections must be excluded. In the case of infection, appropriate antibacterial, antifungal, antiviral and antiparasitic agents must 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
• hyperhydration
• analgesics
• antispasmodics
• manual clot irrigation
• continuous bladder irrigation
• blood transfusions as required
• platelet transfusions as required.

Other measures for the treatment of severe or refractory 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, encourage to void at the first sensation
• 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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