Radiation Cystitis and Hyperbaric Management

Etiology

Radiation is useful for cancer treatment due to its ability to interfere with DNA synthesis and stop rapidly dividing cancer cells from completing mitosis. It also has this same effect on healthy, normally dividing cells surrounding the tumor. Another effect is decreasing blood supply to the irradiated area by causing edema and fibrosis of the vessels (obliterative endarteritis) which can, in turn, lead to necrosis of tissue reliant on those vessels. [4]

Epidemiology

Variation in the incidence of radiation cystitis exists in the current literature. In general, the incidence of delayed radiation effects is estimated at 5% to 10%, and severe hematuria occurs 5% to 8% of the time. Differences in tumor type, the extent of cancer, type of radiation used, and total amount of radiation used create a wide range within the literature.

The average duration from completion of radiation therapy to the onset of symptoms is approximately 31.8 months. It develops more commonly in males than females (2.8:1).[1]

Pathophysiology

It is held that the energy from the radiation affects three different components of the bladder: (1) It affects the urothelium by disrupting tight junctions, increasing elements of the cytoplasm, affecting DNA replication, and causing cellular edema. Once the mucosal cells die and shed, urine can then irritate submucosal cells. (2) It affects bladder vasculature by causing edema and perivascular fibrosis. (3) Finally, radiation affects the detrusor muscle by causing vascular ischemia, increasing fibroblasts and collagen deposition, and causing smooth muscle edema.[2][1]

History and Physical

Acute complaints after completing radiation therapy may include frequency, urgency, dysuria, and hematuria (microscopic or macroscopic). Chronic effects can occur months to years later and are caused by fibrosis. In addition to the symptoms already mentioned, chronic effects can include urinary incontinence from detrusor dysfunction, hydronephrosis, mucosal ulceration, and fistula formation.[1]

Evaluation

The level of severity of symptoms is graded by Radiation Therapy Oncology Group (RTOG) as follows:

• Grade 1 - any evidence of epithelial damage or atrophy, telangiectasia, microscopic hematuria
• Grade 2 - any moderate frequency, generalized telangiectasia, intermittent macroscopic hematuria, intermittent urinary incontinence
• Grade 3 - any severe frequency or urgency, severe telangiectasia, persistent incontinence, reduced bladder capacity < 150 mL, frequent hematuria
• Grade 4 - any necrosis, fistula, hemorrhagic cystitis, reduced bladder capacity < 100 mL, refractory incontinence requiring either catheter or surgical intervention [1]

Workup focuses on ruling out more common etiologies of urinary symptoms. Urinalysis with urine culture and cytology should always be ordered initially to rule out bacterial infection and cancer. If the patient presents with a history of hematuria, a complete blood count (CBC) should be ordered to assess hemoglobin, white blood cell, and platelet counts. Additionally, if the patient has gross hematuria, it is important to assess volume status as well as order prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels. It is also important to assess renal function. A chemistry panel should be ordered to examine electrolyte levels, BUN levels, and creatinine.

Additionally, to further assess the extent of the damage, cystoscopy and renal ultrasound can be utilized. Cystoscopy may show white mucosa with telangiectasia.[3]

Treatment / Management

Treatment of radiation cystitis varies depending on the severity of symptoms. For grade 1 and grade 2 types, symptomatic relief is typically all that is necessary. If frequency and urgency are the predominant symptoms, anticholinergic medications can be used for relief. Additionally, bladder irrigation is usually considered the first-line treatment in all grades of the disease and can be used to remove clots if hematuria is present.[5] Fulguration with alum or silver nitrate may be used inside the bladder as well. [2](B3)

Hyperbaric Oxygen Therapy (HBOT) is another form of noninvasive treatment that has become more prevalent in recent years. This therapy not only targets symptom relief but also has the capability of stopping the progression of the pathologic process. HBOT stimulates angiogenesis, which reestablishes blood flow to areas in danger of necrosis, and helps maintain bladder functionality. Studies have shown a complete response rate ranging from 27% to 100% of patients studied, with most showing more than 75% of patients with a complete response.[3][6]

One study showed that, even with milder symptoms,  patients treated within six months of hematuria onset had  96% complete or partial symptomatic resolution whereas those treated after six months had but a 66% response rate. This is supportive of (albeit not definitive for) the early use of hyperbaric oxygen therapy. [7](B2)

More invasive measures may be necessary if late-stage complications occur or if the radiation cystitis is resistant to more conservative methods. Such situations include persistent hematuria, fistulas, severe detrusor contraction, or hydronephrosis. Failure of more conservative measures leading to cystectomy is associated with a high risk of complications and mortality. Severe complications in almost half (42%) and 90-day mortality is reported to be 16%.

Differential Diagnosis

• Adhesions from prior surgery 

• Degenerative joint disease

• Diverticulitis

• Dysfunctional voiding

• Gastrointestinal neoplasm 

• Hernia 

• Inflammatory bowel disease

• Pelvic floor myalgia

• Vulvodynia