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 Table of Contents  
MANAGING A SIDE EFFECT
Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 66-71

Managing a side effect: Cyclophosphamide-induced hemorrhagic cystitis


Department of Dermatology, KLE Academy of Higher Education and Research, JNMC, Belagavi, Karnataka, India

Date of Web Publication22-Jul-2019

Correspondence Address:
Dr. Bhavana Ravindra Doshi
Department of Dermatology, KLE Academy of Higher Education and Research, JNMC, Belagavi - 590 010, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_31_19

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  Abstract 


Cyclophosphamide is a nonphase-specific cytotoxic agent that can kill cells at any phase of the cell cycle. The drug is metabolized by hepatic cytochrome P450 microsomal enzymes, which results in the formation of the active metabolites phosphoramide mustard and acrolein. It is the acrolein which is responsible for hemorrhagic cystitis as a complication of cyclophosphamide therapy. An early diagnosis and prompt management holds the key in its management.

Keywords: Acrolein, cyclophosphamide, hemorrhagic cystitis


How to cite this article:
Doshi BR, Sajjan VV, Manjunathswamy B S. Managing a side effect: Cyclophosphamide-induced hemorrhagic cystitis. Indian J Drugs Dermatol 2019;5:66-71

How to cite this URL:
Doshi BR, Sajjan VV, Manjunathswamy B S. Managing a side effect: Cyclophosphamide-induced hemorrhagic cystitis. Indian J Drugs Dermatol [serial online] 2019 [cited 2019 Aug 18];5:66-71. Available from: http://www.ijdd.in/text.asp?2019/5/1/66/263095




  Introduction Top


Cyclophosphamide is an alkylating agent which belongs to the family of nitrogen mustard agents that interfere with the growth of rapidly proliferating malignant cells. It is synthesized from a combination of phosphoric acid and inert derivatives of nitrogen mustard. Phosphoramide mustard inhibits DNA replication by means of alkylation.[1] Cyclophosphamide is thought to produce immunosuppressive effects by direct cytotoxic effects on lymphocytes. Cyclophosphamide selectively suppresses B lymphocytes, compared with T lymphocytes.[1] It has an oral bioavailability of >75% and a half-life of 3–12 h. Excretion of metabolites occurs through the renal system.

Besides the extensive use of cyclophosphamide as a chemotherapeutic agent, its introduction as a part of dexamethasone-cyclophosphamide pulse therapy for the pemphigus group of disorders by Pasricha et al. in 1986 revolutionized the therapy for pemphigus. The recommended dosage ranges from 1 to 3 mg/kg/day orally or 0.5–1 g/m2 of body surface area as a monthly intravenous (IV) pulse along with 100 mg of dexamethasone on 3 consecutive days.[2] Besides pemphigus, other dermatological conditions in which cyclophosphamide has been used as pulse therapy either stand alone or orally include cicatricial pemphigoid, bullous pemphigoid, Behcet's disease, pyoderma gangrenosum, scleromyxedema, multicentric histiocytosis, toxic epidermal necrolysis, and microscopic polyangiitis.

Hemorrhagic cystitis (HC) as a complication was described shortly after the clinical use of cyclophosphamide which began in 1958. It occurs in approximately 10%–40% of patients receiving the drug, and sometimes even on withdrawal of the drug.[3] The incidence is higher in those who receive higher individual dose as in the setting of hematopoietic cell transplantation or larger cumulative doses.

Acute HC is characterized by dysuria, frequency, and hematuria, in the absence of bacteriuria. Severe cases may manifest with frank hematuria and passage of clots, which can lead to obstructive uropathy.[4],[5] It usually develops within 24–48 h after drug administration and typically lasts for 5–7 days,[4] although late occurrences up to a month after stoppage of the drug are not uncommon.[4],[6]


  Pathophysiology of Hemorrhagic Cystitis Top


HC occurs as a result of a complex inflammatory response induced by a toxic metabolite acrolein generated during the hepatic metabolism of cyclophosphamide. This is filtered by the kidneys and concentrated in the bladder.[7],[8] Acrolein is a reactive, unsaturated aldehyde which causes cell death via the upregulation of reactive oxygen species that activate inducible nitric oxide synthase, leading to the production of nitric oxide.[9],[10] Both reactive oxygen species and nitric oxide produce peroxynitrites, attack cellular macromolecules (lipids and proteins), and cause DNA strand breaks, triggering the overactivity of DNA repair enzymes.[11],[12] Reactive oxygen species also allow nuclear factor-kappa B to enter the nucleus and turn on the transcription of genes encoding pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-11.[12] This eventually results in the cessation of protein production and damage to the integrity of the urothelium, with morphologic and histologic evidence of swelling, bleeding, and ulceration of the bladder mucosa.


  Risk Factors for Cyclophosphamide-Induced Hemorrhagic Cystitis Top


The potential contributory factors are enlisted below:

  1. Viral infection with BK/JC polyomavirus, adenovirus, or cytomegalovirus[13],[14],[15],[16],[17]
  2. Use of higher doses of busulfan when co-administered with cyclophosphamide as a part of chemotherapy
  3. In individuals who receive higher individual and larger cumulative cyclophosphamide doses,[18] although cases are described after single IV cyclophosphamide doses of 500–600 mg/m2
  4. Genetic polymorphisms in genes involved with cyclophosphamide metabolism,[19],[20] for example, heterozygosity for the ALDH3A1*2 allele, which mediate the degradation of activated cyclophosphamide metabolites, have been associated with a nearly 12-fold increase in the risk of HC compared with the wild-type ALDH3A1 variant.[20]



  Signs and Symptoms of Urinary Bladder Toxicity Top


The signs and symptoms of HC are variable. It may range from mild hematuria and bladder irritation to gross hematuria with clots and life-threatening persistent hemorrhage.

Hematuria

Gross hematuria manifests as red or brown discoloration of urine. In severe cases, the urine may appear thick, and patients may pass blood clots in their urine.

Lower urinary tract symptoms

Urinary urgency, frequent urination of small volumes, sensation of incomplete bladder emptying, and a painful burning sensation associated with urination can be present. In men, bladder spasms may cause referred pain in the glans penis. Suprapubic discomfort may be present. The occurrence of flank or back pain should raise the possibility of upper urinary tract or bladder outlet obstruction. In cases of severe bleeding, urinary retention secondary to blood clots obstructing the bladder neck can occur (also known as “clot retention”).


  Diagnostic Evaluation Top


The diagnosis of HC is based on a typical clinical presentation in the form of hematuria and lower urinary tract symptoms, after excluding other causes such as urinary tract infection, bladder tumor, local tumor extension, and urolithiasis.[21]

Components of diagnostic evaluation

  1. All patients with the signs or symptoms of gross hematuria and/or cystitis should undergo examination of the urine sediment and bacterial culture of a clean catch specimen to confirm hematuria and rule out any bacterial infection in an outpatient setting
  2. In mild cases such as those presenting with hematuria in the absence of infection, if the temporal onset is immediately following a high dose of cyclophosphamide, the drug should be withheld, and the patient should be admitted to ensure good hydration with adequate bladder drainage
  3. In severe cases who manifest with the symptoms of frank bleeding, passage of clots, and hemodynamic instability, a hospital admission is required along with a rapid assessment of hemodynamic stability and ensuring adequate bladder drainage with rigorous hyperhydration. Once the patient is stabilized and adequate bladder drainage is obtained, further evaluation by cystoscopy, urine cytology, and upper urinary tract imaging may be required. The cystoscopy may reveal diffuse oozing of the bladder mucosa with neovascularization and telangiectasias. Alternatively, a computed tomography urogram, or a magnetic resonance urogram, or renal ultrasound and retrograde pyelograms can be done in cases of diagnostic dilemma[22]
  4. Viral cultures, cytology, and special molecular techniques may be required to rule out unusual pathogens in severely immunocompromised patients
  5. A complete blood count, serum creatinine, and coagulation parameters (e.g. prothrombin and activated partial thromboplastin times) should be assessed at the time of presentation in severe cases.



  Prevention of Cyclophosphamide-Induced Hemorrhagic Cystitis Top


1. Hydration is the best treatment for HC prevention. Patients should be instructed to drink at least 2 L of fluid every day and to void at the first sensation. Oral fluids should be ingested prior to sleep, and patients should awaken once during the night to void the bladder. Men should void standing rather than using a bedside urinal in a recumbent position as the posterior wall of the bladder is often involved with HC, possibly because of incomplete emptying of the bladder

2. MESNA or 2-mercaptoethanesulfonate sodium is a thiol compound. Within minutes of IV administration, it is oxidized to a stable inactive disulfide in the serum, but it is reactivated in the kidney. In the urine, it binds to acrolein, creating an inert thioether that is excreted.[23] The serum half-life of MESNA is 90 min, whereas cyclophosphamide has a half-life of 7 h. As a result, multiple doses are necessary. MESNA should be present in the bladder at the time of chemotherapy administration in order to be effective such that it reduces the risk of bladder toxicity by acting as an effective uroprotective agent.[24],[25],[26],[27],[28]

MESNA can be administered intravenously (either continuous or bolus), subcutaneously (continuous),[29] or orally. IV bolus is to be used at a dose equal to 60% of the total high-dose cyclophosphamide, divided into three aliquots and administered prior to and 4 and 8 h following cyclophosphamide administration.[30]

Oral formulations of MESNA demonstrate sustained urinary excretion and urinary bioavailability approaching that of IV MESNA.[31] The rate and amount of MESNA excretion appear to be less variable over time and more prolonged among patients after oral than after IV administration.[32],[33],[34] The protective effect of combined oral and IV MESNA appears to be equivalent to that of IV MESNA alone.[32],[33],[34],[35]

  1. Cancer patients on chemotherapy with cyclophosphamide.


  2. As per guidelines from the American Society of Clinical Oncology (ASCO), it is recommended to use MESNA to prevent HC in all patients in those receiving a high dose of cyclophosphamide.[3],[36],[37]

    Noncancer patients receiving cyclophosphamide.

  3. There are no established guidelines for the use of MESNA in the prevention of bladder toxicity secondary to cyclophosphamide in the treatment of rheumatic diseases or autoimmune bullous disorders as practice patterns vary among clinicians.


3. Forced saline diuresis and continuous bladder irrigation (CBI).

The ASCO expert panel on chemotherapy and radiation therapy protectants recommends MESNA in conjunction with saline diuresis or saline diuresis alone in patients receiving high-dose cyclophosphamide.[37]

Forced saline diuresis with IV normal saline at 250 mL/h and furosemide is sufficient to maintain urinary output >150 mL/h in patients with a high-dose cyclophosphamide conditioning regimen (typically 50 mg/kg or 2 g/m2).[38]

Although highly effective, the use of MESNA and forced saline diuresis does not completely prevent HC in patients receiving high-dose cyclophosphamide. A baseline pretreatment urinalysis and monitoring for the development of gross hematuria and for urine output during treatment[36] along with careful vigilance to pick the earliest symptoms are important to prevent progression to more severe form.


  Treatment of Urinary Bladder Toxicity Top


If hematuria develops despite the preventive measures, treatment options are selected depending on the severity of HC. While there is no consensus on the optimal management of this condition, typically, a step-wise approach to treatment is used, balancing the risks/benefits of each modality and the underlying severity. These include saline bladder irrigation, instillation of intravesical agents, hyperbaric oxygen therapy, urinary diversion, iliac artery angioembolization, and bladder removal (cystectomy). In patients with active bleed, platelet counts should be maintained at >50,000/μl.


  Grading the Severity of Hemorrhagic Cystitis Top


Several investigators and groups have used various grading systems based on the level of intervention required for therapy. Among patients who develop severe HC despite vigorous preventive measures, a few deaths have been reported, although rare.[39]


  Initial Management Top


The initial management of HC varies based on the underlying severity:

  1. For mild HC who present with gross hematuria without clots, adequate bladder emptying, and lower urinary tract symptoms, conservative measures, including hydration and anticholinergic bladder medications (as needed for bladder spasms), may be used in an outpatient setting after urinalysis and culture to exclude infection.[40]
  2. For moderate or severe HC where patients present with the passage of blood clots, initial management includes indoor admission to assess hemodynamic stability, ensuring hydration or blood transfusion if needed, and adequate bladder drainage followed by necessary intervention.


A large-bore (≥22 Fr), three-way Foley catheter is placed to allow for manual clot irrigation with saline. If the urine clears following manual irrigation, subsequent management with hydration alone may be sufficient.

If hematuria or clots persist, CBI with normal saline needs to be initiated. Ensuring adequate fluid outflow from the three-way catheter while on CBI is essential because if the outflow is blocked, the bladder will distend, with the fluid being instilled and present as worsening of abdominal pain or persistent bladder spasms with risk perforation.

If the three-way catheter has repeated obstruction or the patient does not improve with saline CBI over 2–4 days, then the next step is cystoscopy under anesthesia for clot evacuation or fulguration with electrocautery[41] or using a Green Light potassium titanyl phosphate 1064-nm wavelength laser for coagulation of the bleeding vessels.[42],[43]

For persistent or moderate hematuria

If despite the above measures, there is persistence of gross hematuria, with or without clots, additional interventions, such as intravesical instillations, may be required. While there is no consensus on the optimal management of this condition, typically, a step-wise approach to treatment is used, balancing the risks/benefits of each modality and the severity of the condition.

Alum

Given the efficacy and tolerable side effect profile of intravesical alum instillation, it is commonly the first intravesical therapy utilized when other conservative measures have failed.

Alum (aluminum ammonium sulfate or aluminum potassium sulfate) is an astringent that induces hemostasis by precipitating protein over the bleeding surface. It has a low cell permeability; hence, its action is limited to the cell surface and interstitial spaces. Prior to intravesical alum instillation, complete clot removal from the bladder has to be ensured.

It is to be used as a 1% solution (50 g of alum dissolved in 5 L of sterile water) to continuously irrigate the bladder via a three-way Foley catheter (250–300 cc/h).[44]

Side effects are local irritative voiding symptoms.[45] Toxicity from systemic absorption is less common, except in those with chronic kidney disease.[46],[47],[48],[49] Clinically, aluminum toxicity may present with mental status changes, malaise, speech changes, and seizure.[47]

Aminocaproic acid

It is a synthetic lysine that decreases fibrinolysis by competitively inhibiting plasminogen and plasmin.[50] For patients with HC, it is administered intravesically as 200 mg of aminocaproic acid per 1 L of normal saline, or orally in divided doses of 100–150 mg/kg/day.[51],[52],[53] Potential side effects are thrombotic complications, rhabdomyolysis, and myopathy.

Silver nitrate

Silver nitrate can be used for intravesical instillation; it acts by getting converted into nitric acid on instillation, which causes chemical cauterization of the urothelium. The preparation is made using sterile water in concentration ranging from 0.01% to 1% for use. However, for instillation of concentrations ≥0.5%, anesthesia is required.[54]

Potential side effect includes obstruction from precipitation after instillation; hence, a cystogram should be performed to rule out ureteral reflux prior to intravesical instillation.[55]

Pentosan polysulfate sodium

Pentosan polysulfate sodium (PPS) is a low-molecular-weight heparin-like compound with anticoagulant and fibrinolytic effects that has been approved for the symptomatic treatment of interstitial cystitis. It is administered as oral PPS 100 mg three times a day. The proposed mechanism of action is reconstitution of the deficient protective glycosaminoglycan layer over the urothelium.[56]


  Severe And/or Refractory Hemorrhagic Cystitis Top


Urinary diversion

Urinary diversion can be performed of a temporary or permanent nature with percutaneous nephrostomy tube placement in stable patients who have failed more conservative measures.

Intravesical formalin instillation

As formalin is caustic, long-term risk of bladder dysfunction, ureteral stricture, and injury to the genital skin and perineum can occur if they are not adequately protected; hence, formalin is reserved for severe cases of HC following failure of other intravesical therapies.

Formalin is a 37% aqueous solution of formaldehyde which acts by hydrolyzing proteins and coagulating the tissue on a superficial level, controlling hemorrhage in the mucosa and submucosa. Instillation is initiated with 1% formalin under general or regional anesthesia, and if the treatment is not successful, the dose is escalated. Instillations are performed following a cystogram (to ensure that there is no bladder perforation or ureteral reflux), under low pressure (<15 cmH2O), and with a short dwell time (10–15 min).[57],[58],[59]

With instillation, the catheter needs to be kept in slight tension to occlude the bladder neck and prevent urethral exposure. If ureteral reflux is present, the ureters should be obstructed with occlusive catheters prior to formalin instillation.

Vascular interventions and extirpative surgery

They are to be undertaken in patients with persistent severe HC despite previous measures, or in those with life-threatening bleeding.

Selective iliac artery embolization

Selective iliac artery embolization has been successfully tried in cases of refractory HC or in unstable patients, with a resolution of bleeding in up to 92% of cases.[60],[61],[62] It is performed by placing an occlusive material (e.g. gel foam and coils) in the anterior division of the internal iliac artery, which leads to occlusion of blood supply by subsequent branches to the bladder via the vesical arteries. Rare complications of the procedure include bladder necrosis and embolization of the occlusive material to distal arterial branches.[63]

Cystectomy

Very rarely, surgical removal of the urinary bladder may be required to control hemorrhage.[64] This is done with a simple cystectomy and ileal or transverse colon conduit formation.[64],[65],[66]


  Conclusion Top


Although HC is a rare complication of cyclophosphamide therapy, the possible interventions to avoid and manage this complication have been discussed above. A strong suspicion and prompt vigilance is important in its management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Pathophysiology ...
Risk Factors for...
Signs and Sympto...
Diagnostic Evalu...
Prevention of Cy...
Treatment of Uri...
Grading the Seve...
Initial Management
Severe And/or Re...
Conclusion
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