Haemorrhagic Cystitis

Both alkylating agents, cyclophosphamide and ifosfamide, have the potential to induce severe cases of haemorrhagic cystitis. The pathogenesis of haemorrhagic cystitis associated with cyclophosphamide is attributed to acrolein, a metabolite of cyclophosphamide that infiltrates the uroepithelium, instigating DNA damage and ensuing tissue necrosis. Approximately 1-6% of patients administered cyclophosphamide will manifest gross haematuria, with mortality rates for severe haemorrhagic cystitis ranging from 10-30%. The onset of symptoms can vary significantly, with patients exhibiting signs immediately after treatment or even years later. Moreover, symptoms may persist for an extended duration despite therapeutic intervention.

Prevention

The prevention of haemorrhagic cystitis entails proactive measures such as adequate hydration and forced diuresis, aiming to minimize the duration of acrolein exposure to the bladder. Hydration protocols typically commence 12-24 hours preceding cyclophosphamide administration, with the objective of achieving a urine output of 100 ml/m2/hr. Should urine output fall below the desired threshold, diuretics are administered to maintain the target output. Additionally, the inclusion of mesna in cyclophosphamide and ifosfamide treatment regimens has significantly mitigated the risk of haemorrhagic cystitis. Mesna is typically administered at 100-160% of the cyclophosphamide dosage, either via continuous infusion or intermittently, usually 15-30 minutes prior to cyclophosphamide administration.

Treatment

The treatment of severe haemorrhagic cystitis encompasses a range of approaches, including pharmacologic interventions such as aminocaproic acid, as well as the instillation of intra-vesicular agents like alum, silver nitrate, and formalin. Additionally, treatment modalities may involve clot evacuation, continuous bladder irrigation (CBI), hyperbaric oxygen therapy, and in extreme cases, cystectomy.

Before initiating pharmacologic treatments, it is imperative to evaluate patients for viral infections, particularly adenovirus and BK virus, as these pathogens can exacerbate haemorrhagic cystitis, particularly in immunocompromised individuals. This pre-treatment assessment ensures the selection of the most appropriate therapeutic approach tailored to the individual patient’s needs and circumstances.

First line treatment is CBI with a large bore three-way Foley catheter. This will remove existing clots, making subsequent treatment more successful. If clots are not removed by CBI, manual removal may be necessary. If patients continue to bleed after CBI, intra-vesicular administration of alum, silver nitrate or prostaglandin may be necessary. Alum acts as a local astringent causing decreased edema and inflammation.

A 1% solution administered through a three-way Foley at a rate of 300-1000 ml/hr. is common, although a 2-4% solution may achieve better results. Varying rates of success from 50-100% response have been demonstrated with alum therapy. Side effects are usually bladder spasm, suprapubic pain, urinary frequency or retention, and can be controlled with analgesics. Patients with renal dysfunction or those receiving prolonged alum irrigation should be monitoring for mental status changes as aluminum toxicity, although rare, can occur.

Carboprost tromethamine, a PGF2 prostaglandin, acts to repair the microvasculature and epithelium of the bladder. A solution of carboprost is instilled 3-4 times daily, allowed to dwell for 1-4 hours for 5-7 days. About half of patients respond, with a median response of 2-5 days. Side effects include bladder spasm and discomfort.

Silver nitrate acts to cauterize the bladder mucosa. A solution is instilled for 10-20 minutes, followed by bladder irrigation. The procedure is extremely painful, and patients should be anesthetized prior to treatment. The success of the procedure is variable and short lived. Systemic therapy with the antifibrinolytic aminocaproic acid has also been employed. The usual dose is a 5-gm loading dose followed by a continuous infusion of 1 gm/hr until bleeding stops. This will increase systemic clotting, thus decreasing haemorrhaging, but the risk that formed clots may be too large to pass through the Foley does exist.

Formalin, also administered by direct instillation, acts as a local coagulant to bladder tissue. Administration causes significant pain and patients must be anesthetized. Although effective, this therapy should only be used in patients in whom other therapies have failed as repeated administration of formalin can cause reflux and hydronephrosis of the kidney. Cystoscopy to evaluate bladder anatomy should be performed prior to formalin installation.

Hyperbaric oxygen, investigated in case reports, should, in theory, increase oxygenation of tissues and promote healing. This therapy, usually delivered daily for multiple days, has decreased gross haematuria in case reports.

Invasive surgical therapies are reserved for patients who have failed less invasive measures discussed previously. Urinary diversion, arterial embolization and cystectomy have all been used for intractable haemorrhagic cystitis.

Suggested Guidelines regarding Chemotherapy / Mesna

Microscopic Haematuria

1. Transient microscopic haematuria (no more than 2 abnormal urinalyses on two separate days during a course of therapy): no modification of the cyclophosphamide/Ifosfamide or Mesna.
2. Persistent microscopic haematuria (> 2 abnormal urinalyses during a course of therapy):
   • Do not modify the cyclophosphamide/Ifosfamide dose.
   • Give hydration and Mesna (increase dose to cover 24 hours) continuous infusion over 24 hrs.

Gross Haematuria

• Transient gross hematuria during or following a course of therapy (only one episode, which clears to less than gross hematuria):
  • Do not modify the cyclophosphamide/Ifosfamide dose.
  • Give hydration and Mesna and continuous infusion (increase dose to cover 24 hours) over 24 hours following each dose of cyclophosphamide/Ifosfamide.
• Persistent gross haematuria after completion of a course of therapy:
  • Hold subsequent cyclophosphamide/Ifosfamide until the urine clears to less than gross haematuria.
  • Reinstitute cyclophosphamide /Ifosfamide at full dose, with the Mesna changed to a continuous infusion (increase dose to cover 24 hours) over 24 hours following each dose of cyclophosphamide/Ifosfamide.
  • If gross haematuria does not clear to microscopic haematuria or less, withhold further cyclophosphamide/Ifosfamide therapy.
• Persistent gross haematuria occurring during a course of chemotherapy.
  • Withhold further cyclophosphamide/Ifosfamide until the next course of therapy.
  • If the gross haematuria clears to microscopic haematuria or less, subsequent courses of cyclophosphamide/Ifosfamide may be administered at full dose, with Mesna changed to a continuous infusion over 24 hrs.
• Occurrence of a second episode of gross haematuria or persistence of microscopic haematuria on the continuous infusion regimen.
  • Continue the cyclophosphamide/Ifosfamide when the urine clears less than gross haematuria.
  • Double the loading dose of Mesna and the subsequent dose.
  • Continue to give Mesna by continuous infusion for 48 hours after the last dose of cyclophosphamide/Ifosfamide.
• Persistent gross haematuria in the face of this “double dose, continuous infusion regimen”: Discontinue cyclophosphamide/Ifosfamide.

References

• Cassandra B, Amanda B. Life threatening toxicities of chemotherapies and immunomodulating medications. Critical Care Medicine. Decision Support in Medicine.