Radiation cystitis

Radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region.

Radiation cystitis is a complication of radiation therapy to pelvic tumors. 

 

Manifestations of radiation cystitis can range from minor, temporary, irritative voiding symptoms and painless, microscopic hematuria to more severe complications, such as gross hematuria; contracted, nonfunctional bladder; persistent incontinence; fistula formation; necrosis; and death.

 

Cobalt therapy, because of its low energy, requires high doses to deliver adequate radiation to the tumor, results in higher doses to healthy structures near the target and, thus, high complication rates. 

 

Newer techniques and energy sources minimize collateral radiation to healthy structures: conformal beam therapy and computed tomography (CT) or ultrasonography-guided brachytherapy. 

 

Concomitant use of chemotherapeutic agents may increase the risk of developing bladder injury from radiation. 

 

Bladder radiation  long-term complications depends on:

Volume and area of bladder affected with dose rate (< 0.8Gy/h decreases risk of cystitis) and daily fraction size (doses >2Gy/fraction increase risk).

 

Toxicity increases when the total dose received exceeds 60Gy to the bladder.

 

Conformal beam therapy allows higher doses to the target tissue while maintaining lower total dose delivered to the bladder.

 

The overall frequency of radiation cystitis 1 year after treatment of bladder cancer is 9-21%.

 

The overall frequency of radiation cystitis 1 year after treatment of cervical cancer is 3-6.7%.

 

The incidence rate of hemorrhagic cystitis after radiation for prostate cancer is approximally 11%%.

 

Intensity-modulated radiotherapy (IMRT) has been shown to deliver higher doses to the target area while reducing complications. 

 

After treatment for prostate cancer, the incidence of bladder complications is unchanged from IMRT or standard radiation.

 

Radiation cause vascular changes: Subendothelial proliferation, edema, and medial thickening may progressively deplete the blood supply to the irradiated tissue. 

 

Tissue hypoxia and necrosis may develop due to collagen deposition causing severe scarring and blood vessel obliterate.

 

Fibrosis leads to impaired revascularization.

 

Ultimately mucosal ischemia and epithelial damage occur.

 

Exposure to the caustic effects of urine may cause further submucosal fibrosis.

 Bladder ulcer formation, radiation neuritis, and postradiation fibrosis may cause pain and discomfort.

 

Later histological  findings include fibrovascular changes  with luminal occlusion, vascular ectasia, and necrosis of bladder blood vessel walls. 

 

Such changes may produce ischemia and fibrosis leading to loss of bladder muscle fibers and to dysfunctional voiding and denervation supersensitivity causing abnormal neural stimulation of the bladder.

 

Radiation complications involving the bladder are graded on a scale devised by the Radiation Therapy Oncology Group (RTOG):

Grade 1 – Any slight epithelial atrophy, microscopic hematuria, mild telangiectasia

Grade 2 – Any moderate frequency, generalized telangiectasia, intermittent macroscopic hematuria, intermittent incontinence

Grade 3 – Any severe frequency and urgency, severe telangiectasia, persistent incontinence, reduced bladder capacity (< 150mL), frequent hematuria

Grade 4 – Any necrosis, fistula, hemorrhagic cystitis, bladder capacity (< 100mL), refractory incontinence requiring catheter or surgical intervention

Grade 5 – Death

 

Because radiation cystitis can mimic many different diseases, a complete evaluation of the urinary tract is required. 

 

Evaluation includes:

Urinalysis to assess for hematuria and pyuria and to measure urine pH.

Urine culture to confirm or rule out infection.

 

Urinary cytology to screen for tumor.

 

If hematuria is present cystoscopy and renal imaging are also indicated to rule out other possible causes of genitourinary (GU) bleeding. 

 

Biopsy of the bladder should be avoided 

because it may cause bleeding or even fistula formation. 

 

Bladder biopsies may be indicated if a suspicious lesion or recurrent tumor is suggested.

 

Urodynamic studies can help to assess  decreased bladder volume, postvoid residual urine, and detrusor instability, which may be present in radiation cystitis.

 

Cystoscopy confirms the diagnosis and to rule out other conditions. 

 

Hemorrhagic cystitis is a serious complication of radiation cystitis and is evaluated  by cystoscopy for both diagnosis and for clot evacuation if bleeding is heavy. 

 

Cystoscope can resolve hemorrhagic symptoms in up to 61% of patients at initial presentation.

 

Continuous bladder irrigation may be used either alone or in conjunction with hyperbaric therapy. 

 

Bladder irrigation with formalin is a painful procedure and requires a general anesthetic. 

 

Formalin, a 37% solution of formaldehyde and water is a tissue fixative used for hemorrhagic cystitis.

 

Bladder irrigation with formalin response rate is 52-89%,  and the recurrence rate is 20-25%.

 

Alum causes protein precipitation in the interstitial spaces and cell membranes, contracting of the extracellular matrix and tamponade of bleeding vessels. 

 

Alum has a response rate of 50-80%, and the recurrence rate is 10%.

 

If continuous bladder irrigation alone is not successful, bladder instillation with agents including  1% alum, aminocaproic acid and 1-10% formalin. 

 

Aminocaproic acid inhibits plasminogen activation, thus decreasing plasmin, and is placed intravesically according to the severity of bleeding and continued for 24 hours after bleeding stops.

 

Aminocaproic acid has a response rate of 91%, and recurrences have not been reported. 

 

Cystoscopy is useful in the initial management of hemorrhagic cystitis, both diagnostically to rule out other pathology and for clot evacuation if bleeding is heavy. 

 

Cystoscope can resolve symptoms in up to 61% of patients at initial presentation.

 

If symptoms persist, however, cystoscopic intervention is rarely successful.

 

Cystoscopy findings  include:

Telangiectasia

Diffuse erythema

Increased submucosal vascularity

Mucosal edema

pallor caused by increased collagen deposition.

Cystoscopic findings in chronic radiation injury can be similar to those in acute injury.

Acute radiation cystitis is usually self-limiting.

 

Acute radiation cystitis is associated with:

detrusor instability in 40-50% of patients.

Decreased peak flow rate

Decreased bladder compliance

Decreased bladder volume, with approximately 20% volume reduction.

 

Severe bladder complications of radiation injuries are difficult to manage because they tend to be chronic, recurrent and are occasionally refractory to therapy. 

 

Complications of radiation cystitis include: hemorrhagic cystitis in 3%-5%, of cases, vesical fistula, 2%, and bladder neck contracture at 3%-5%.

 

Symptoms associated with radiation cystitis are divided  into acute and late-phase, or chronic, symptoms. 

 

Acute radiation cystitis is managed conservatively with symptomatic therapy or observation. 

 

Late radiation cystitis can develop months to years after radiation therapy.

 

Late radiation cystitis presents principally as hematuria, which ranges from mild to life-threatening. 

 

Symptomatic frequency and urgency are treated with anticholinergic agents. 

 

Phenazopyridine can be used to provide symptomatic relief.

 

Phenazopyridine is an azo dye that has local anesthetic or analgesic action n the bladder.

 

Phenazopyridine acts directly on urinary tract mucosa when excreted.

 

If radiation cystitis is not severe, pentosan polysulfate sodium (Elmiron), with or without pentoxifylline for pain, is a considered  first treatment.

 

Pentosan polysulfate sodium protects transitional epithelium by restoring the bladder glycosaminoglycan layer. 

 

Pentosan polysulfate sodium response rate in radiation cystitis is 71-100%, and the recurrence rate is 23%. 

 

Sodium pentosan polysulfate is a pregnancy category B drug.

 

The use of endoscopic injection sclerotherapy has been reported with good results patients with intractable hemorrhagic cystitis: injection of a sclerosing agent 1% ethoxysclerol into the bleeding areas to control the severe hematuria.

 

Intravesical agents are used for late radiation cystitis patients. 

 

Hyperbaric oxygen (HBO) therapy yields the most consistent results in severe cases.

Reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomized and retrospective studies.