Radiation cystitis

Radiation cystitis is a medical term to describe the side effect of inflammation and subsequent destruction to the normal anatomy of the urinary bladder at the cellular level after the use of radiation in the treatment of multiple cancer types, including, most commonly, pelvic cancers. The urinary bladder can be irradiated intentionally for the treatment of bladder cancer or incidentally for the treatment of other pelvic malignancies. 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.

Radiation therapy can be used for primary bladder cancer as well as for tumors in many organs surrounding the bladder, such as the colon, rectum, ovaries, uterus, and prostate. When the primary tumor is not located in the bladder, this leads to unintentional radiation exposure to the healthy bladder tissue.

Damage from the treatment can either be acute (less than six months from radiation therapy completion) or delayed (more than six months after treatment) and can have varying levels of irritation and functional impairment to the bladder mucosa. If on the mild end of the spectrum, symptoms may include increased frequency, urgency, and possibly some dysuria. Infection should be ruled out with a urinalysis which may show microscopic hematuria. These symptoms can resolve over time.

On the other end of the spectrum, patient’s may experience symptoms such as urinary incontinence, gross hematuria, and progression of damage to the extent of fistula formation or necrotic bladder tissue. The treatment varies on the degree of symptoms. Overall, radiation cystitis can be detrimental to a patient’s wellbeing after already having gone through a great deal in regards to cancer treatment. Health care providers are becoming more aware of the drastic effects a dysfunctional bladder can have on overall quality of life, but more investigation needs to be performed to best tailor radiation therapy while avoiding side effects such as radiation cystitis.

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 ¹. 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.

Acute radiation cystitis is usually self-limiting and is generally managed with conservative symptomatic therapy or observation. Late radiation cystitis, which can develop months to years after radiation therapy, presents principally as hematuria, which ranges from mild to life-threatening ². A variety of intravesical agents has been used for these patients. Hypebaric oxygen therapy has shown success in severe or refractory cases ³.

Radiation cystitis grading

The level of severity of radiation cystitis symptoms is graded by Radiation Therapy Oncology Group as follows ⁴:

• 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 directly due to hemorrhagic cystitis

Radiation cystitis symptoms

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.

In general, symptoms associated with radiation cystitis can be grouped into acute and late-phase, or chronic, symptoms. Acute symptoms are caused by the inflammatory response to ionizing radiation and are similar to those for any inflammatory process of the bladder. They consist of urgency, frequency, dysuria, and hematuria.

Late-phase, or chronic, symptoms are the end result of the inflammatory process caused by radiation. Ischemia and fibrosis are the main factors responsible for symptoms. As a result, new symptoms can occur years after initial therapy, resulting from bladder contraction, ulcer formation, fistulas, and bladder dysfunction. Therefore, clinical presentation can include any of the following urinary symptoms:

• Frequency
• Urgency
• Dysuria
• Hematuria
• Incontinence
• Hydronephrosis
• Pneumaturia (air bubbles in urine)
• Fecaluria (feces in urine)

Radiation cystitis diagnosis

In patients presenting with hematuria post-radiation, a thorough assessment is needed to rule out secondary causes before a diagnosis of radiation cystitis can be made. Radiation cystitis can mimic many different diseases. Neoplasia, urinary tract infection (UTI) and stone disease produce similar findings. Consequently, a complete evaluation of the urinary tract is required. The initial evaluation should include the following:

• 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 the patient has hematuria, a complete blood count (CBC) is required to assess hemoglobin, hematocrit, and adequate platelet count. Gross hematuria is an indication to evaluate volume status, coagulation status, and the need for red blood cell (RBC) transfusion. Cystoscopy and renal imaging are also indicated to rule out other possible causes of genitourinary bleeding. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are needed to rule out coagulopathies if the patient is bleeding.

A white blood cell (WBC) count is necessary to assess for infection if the patient is febrile. Electrolytes, blood urea nitrogen (BUN), and creatinine levels are needed to assess renal function; obstructive uropathy may result from stricturing of the urinary tract and poor emptying. Urodynamics may be required if a patient presents with more complicated symptoms, but most symptoms can be evaluated by a thorough history and physical examination.

Biopsy

Avoid bladder biopsy because it may cause persistent bleeding or even fistula formation. However, judicious use of bladder biopsies may be indicated if a suspicious lesion or recurrent tumor is suggested.

Urodynamic studies

Urodynamic studies are needed only when the diagnosis remains unclear after the history and physical examination. Urodynamics can help to assess for decreased bladder volume, postvoid residual urine, and detrusor instability. All are potentially present in radiation cystitis but are not specific for the disease.

Reported findings in acute cases include the following:

• Detrusor instability (40-50% of patients)
• Decreased peak flow rate
• Decreased bladder compliance
• Decreased bladder volume (approximately 20% volume reduction)

After the acute phase has passed (6 months), most bladder parameters return to normal. Some authors report a persistent loss of bladder compliance; however, it is not significantly different from that in control subjects.

Cystoscopy

Cystoscopy in patients with new-onset or suspected radiation cystitis can be both diagnostic and therapeutic. Cystoscopy is used to confirm the diagnosis and to rule out other conditions, such as bladder cancer or other recurrent metastatic tumors. Cystoscopy can be combined with retrograde pyelography, if needed.

On cystoscopy, acute radiation injury is characterized by changes such as the following:

• Telangiectasia
• Diffuse erythema
• Prominent submucosal vascularity
• Mucosal edema

The appearance of diffuse erythema, telangiectasia with or without ulcerations can help confirm the diagnosis of radiation cystitis. At the time of cystoscopy, fulguration of suspected vascular lesions may provide control of hematuria. In a case series assessing the effectiveness of cystoscopy and fulguration for hematuria control in patients with either radiation- or chemotherapy-induced symptoms, 61% (20/33) of patients achieved resolution of symptoms after initial endoscopic treatment ⁵. Only 36% (4/11) of patients who had refractory symptoms responded to a second cystoscopy and fulguration.

Multiple small case series have assessed alternatives to fulguration with Greenlight laser, KTP laser treatment, and argon beam coagulator ⁶. All series report laser therapy being well-tolerated and having a beneficial effect. In the future, they may play a larger role in the treatment of radiation cystitis; however, until larger studies can confirm their safety and effectiveness, they remain experimental in nature. Additional studies have investigated intravesical hemostatic gelatin matrix (Floseal) in six patients and was noted to be beneficial ⁷. Fibrin glue has been trialed in the treatment of post-hematological stem cell transplant patients and found to reduce hematuria ⁸, but it has yet to be investigated in the radiation cystitis population beyond individual case studies ⁹.

Imaging studies

Imaging studies may consist of intravenous pyelography (IVP), CT urography, or renal ultrasonography. IVP (intravenous pyelography) is useful to evaluate anatomic abnormalities of the genitourinary tract (eg, stricturing, fistula formation). If hematuria is present, IVP or CT urography is needed to rule out other causes of bleeding, such as calculus disease and neoplasia. As an alternative, ultrasonography can be used to assess for hydronephrosis due to scarring, renal tumors (as another cause of bleeding), and calculus disease.

CT scanning may also help in the diagnosis of bladder fistulas. Findings in patients with fistulas include the following ¹⁰:

• Intravesical air (90%)
• Passage of orally or rectally administered contrast medium into the bladder (20%)
• Focal bladder-wall thickening (90%)
• Thickening of adjacent bowel wall (85%)
• Extraluminal mass that often contains air (75%)

Radiation cystitis treatment

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 ¹¹. Fulguration (destruction of small areas of tissue) with alum or silver nitrate may be used inside the bladder as well ¹².

The use of endoscopic injection sclerotherapy has been reported with good results in a limited number of patients with intractable hemorrhagic cystitis ¹³. This treatment involves the injection of a sclerosing agent (eg, 1% ethoxysclerol) into the bleeding areas to control the severe hematuria in patients with otherwise intractable bleeding that is not responding to simpler methods. Further studies are necessary to determine the exact role of this novel type of therapy in selected patients with radiation cystitis.

Gacci et al ¹⁴ reported that instillation of the combination of hyaluronic acid and chondroitin sulfate was effective in reducing nocturnal voiding frequency in men with bladder pain following radiation therapy for prostate cancer. Study patients underwent bladder instillation therapy with hyaluronic acid and chondroitin sulfate weekly for the first month and, afterwards, on week 6, 8 and 12.

If symptoms become more severe or oral therapy is not satisfactory, the available literature suggests that Hyperbaric Oxygen Therapy yields the most consistent results ¹⁵.

Hyperbaric Oxygen Therapy is another form of noninvasive treatment that has become more prevalent in recent years. Hyperbaric Oxygen Therapy not only targets symptom relief but also has the capability of stopping the progression of the pathologic process. Hyperbaric Oxygen Therapy 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 ¹⁶.

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 ¹⁷.

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%.

Medications for radiation cystitis

Symptomatic frequency and urgency are best treated with anticholinergic agents. Once all other causes of dysuria have been ruled out, phenazopyridine can be used to provide symptomatic relief.

If the symptoms of radiation cystitis are not severe but are significant enough for a patient to seek help, pentosan polysulfate sodium (Elmiron), with or without pentoxifylline for pain, is a reasonable first step ¹⁸.

A randomized, double-blind, placebo-controlled pilot study in 41 men receiving external beam radiation therapy for prostate cancer found that ingestion of cranberry capsules may help prevent or reduce the severity of radiation cystitis, particularly in patients those on low-hydration regimens or with baseline urinary symptoms. The capsules were standardized to contain 72 mg proanthocyanidins. Study patients took one capsule a day at breakfast during treatment and for 2 weeks after treatment completion ¹⁹.

Alum irrigation

Intravesical aluminous salts act as an astringent agent and exert their effect through protein precipitation causing decreased capillary permeability, contraction of intercellular space, vasoconstriction, and hardening of the capillary endothelium ²⁰. It is typically administered as a 1% concentration of alum mixed with sterile water, irrigated through the bladder at 250–300 ml per hour, at a duration up to the discretion of the observing clinician. Ideally, the bladder should be irrigated free of clots prior to initiation of therapy. Historical case series have demonstrated the efficacy and tolerability of intravesical alum for a wide range of etiologies and presentations of intractable bladder hemorrhages ²¹. The common side effects are bladder spasms, suprapubic discomfort, and clotting of the catheter due to precipitant formation. Individual case studies have reported a risk of aluminum toxicity in individuals in renal failure ²².

The most recent, and largest case series reported the use of alum irrigation in 40 patients (38 of whom had previous radiation treatment) with symptoms of hemorrhagic cystitis ²³; 60% of these patients demonstrated an improvement in their symptoms and required no further treatment prior to discharge. The treatment was well-tolerated and 90% of patients were able to receive their treatment as prescribed. Two patients discontinued due to inability to tolerate bladder spasms and two for altered level of consciousness. Overall, 35% of patients experienced bladder spasms. Asymptomatic elevation in serum aluminum was detected in one patient that resolved on discontinuation of the treatment. At a median followup of 16.5 months, only 32% of patients required no further treatment, bringing the durability of this treatment into question.

Hyaluronic acid

Hyaluronic acid is a mucopolysaccharide whose therapeutic benefit is believed to be mediated by the repair of the normal glycoaminoglycan layer of the bladder when applied as intravesical installations. It has been shown that radiation leads to defects in this protective layer, leading to chronic inflammatory changes and delayed or prevented healing of urothelial cells ²⁴. Its use as an intravesical agent is well-studied in the treatment of interstitial cystitis and painful bladder syndrome, where it was recently recommended as a treatment option in the Canadian Urological Association guideline ²⁵.

One of the few randomized trials comparing treatment modalities for radiation cystitis randomized 36 patients to either intravesical therapy with hyaluronic acid or treatment with hyperbaric oxygen therapy ²⁶. In the hyaluronic acid group, patients received intravesical therapy once weekly for one month and then monthly for two months. Patients in the hyperbaric oxygen therapy group received daily treatments for 30 treatments. Followup assessment of symptoms were done at six, 12, and 18 months following therapy. Complete resolution of hematuria was noted in 88%, 75%, and 50% of hyaluronic acid patients at those intervals and in 75%, 50%, and 45% of patients in the hyperbaric oxygen therapy group. The difference was not statistically significant at any interval and the author concluded the hyaluronic acid therapy was at least as effective as hyperbaric oxygen therapy in the treatment of hematuria.

A prospective, observational study of 20 patients undergoing treatment with intravesical hyaluronic acid compared grading of radiation cystitis, including hematuria, as per Radiation Therapy Oncology Group classification (scale 1–5) before treatment and again three months after the completion of six scheduled treatments ²⁷. The mean radiocystitis scores before and after hyaluronic acid treatment were 2.70 and 1.45, respectively, with only minor side effects described. It is notable that no patients with grade 4 or 5 toxicity, considered severe symptoms, were included in this study. Beyond hematuria, recent prospectively collected data suggests that intravesical treatment with hyaluronic acid in combination with chondroitin sulfate (another glycosamniglycan) produces a clinically significant improvement in post-radiation lower urinary tract symptoms and bother. In a study published by Gacci et al ²⁸, 80 patients with previous radiation therapy and new-onset or worsening lower urinary tract symptoms were shown to have a statistically significant reduction in urgency, frequency, nocturia, and bladder pain, as measured by patient-reported outcomes after intravesical treatment with hyaluronic acid and chondroitin sulfate.

Other intravesical agents

Intravesical instillation of the antifibrinolytic agent epsilon aminocaproic acid was shown to improve hematuria in 34 patients in case series of 37 patients with intractable bladder hemorrhage, most of whom had either radiation- or cyclophosphamide-induced cystitis; however this has not been repeated in contemporary studies since its publication in 1992 ²⁹. Intravesical instillations of prostaglandins have been demonstrated in several smaller case series to be effective in treating hemorrhagic cystitis secondary to treatment with cyclophosphamide, but there are no large studies to suggest their effectiveness in radiation cystitis ³⁰. Silver nitrate instillations have been tried and were found to be ineffective in limiting radiation cystitis ³¹.

Sodium pentosan polysulfate

Sodium pentosan polysulfate is a semisynthetic polyscaccharide formulated as an oral medication that serves as a synthetic glycosaminoglycan. It adheres to the bladder mucosa, where it supplements the bladder’s own glycosaminoglycan layer in a similar fashion as intravesical treatment with hyaluronic acid. It has been previously shown to be effective in the treatment of interstitial cystitis ³². The largest study to assess its effectiveness in hematuria secondary to radiation followed 60 consecutively enrolled patients who were treated with 100 mg orally of sodium pentosan polysulfate three times daily ³³. In 10 patients, hematuria was noted to have resolved completely, and there was partial resolution in 21 patients. However, the applicability of this study was limited by the large number of participants not available for followup or who passed away during the study from causes unrelated to hematuria. Two other small case series have also demonstrated the benefits of oral sodium pentosan polysulfate ³⁴. Its usefulness was noted primarily by its safety, tolerability, and ease of administration; however, the onset of action was found to be 1–8 weeks, limiting its use in the acute setting. A recent case series has suggested a risk of pigmentary maculopathy associated with long-term chronic use of sodium pentosan polysulfate (median duration of 186 months) ³⁵.

Hyperbaric Oxygen Therapy

Therapy for radiation cystitis is primarily aimed at relief of symptoms. The exception is Hyperbaric Oxygen Therapy, which can potentially reverse the changes caused by radiation. Hyperbaric Oxygen Therapy stimulates angiogenesis, which reverses the vascular changes induced by ionizing radiation ³⁶. The ability of Hyperbaric Oxygen Therapy to preserve bladder function and the noninvasive nature of this treatment are features that favor its use. However, if significant fibrosis and ischemia have already occurred, Hyperbaric Oxygen Therapy therapy does not reverse the changes and only prevents further injury ³⁷.

Hyperbaric Oxygen Therapy has a reported response rate of 27-92%, and the recurrence rate is 8-63% ³⁸. In adults, Hyperbaric Oxygen Therapy is administered as 100% oxygen at 2-2.5 ATM. Each session lasts from 90-120 minutes, and patients receive Hyperbaric Oxygen Therapy sessions 5 days weekly for a total of 40-60 sessions. Hyperbaric Oxygen Therapy therapy is a pregnancy category A treatment.

Nakada and colleagues ³⁹ reported good long-term outcomes with Hyperbaric Oxygen Therapy treatment in 38 patients with radiation cystitis following irradiation of prostate cancer. At 7-year follow-up, objective and subjective improvements in symptoms were seen in 72-83% of patients. No recurrence was seen in 28 patients (74%); these patients had received an 18% lower radiation dose than patients who did experience recurrence.

Experimental therapy

WF10, an intravenously administered macrophage regulator, has shown promising results for treatment and decreased recurrence of radiation cystitis in two studies published at a single center ⁴⁰.

Two small case studies explored the use of estrogen in treatment of hemorrhagic cystitis of multiple etiologies ⁴¹. While both showed reduction in hematuria, larger studies are needed before recommendations regarding effectiveness or safety can be made.

There is conflicting evidence that may point to a role for cranberry juice in preventing acute urinary symptoms in patients undergoing pelvic radiation; however, there is no data to suggest it has a role in management of late-effect radiation cystitis ⁴².

There is a growing body of evidence exploring the use of tranexamic acid in the control of hemorrhage of multiple etiologies. Its use has previously been suggested in the management of radiation cystitis ⁴³. A randomized control trial recently assessed the use of intravenous tranexamic acid in controlling of hematuria of multiple causes in the acute setting. It found a decreased time on continuous bladder irrigation until resolution of hematuria; however, no significant difference in blood loss or transfusions rates were noticed in the treatment group ⁴⁴. While further studies may demonstrate a benefit in treatment of patients with radiation cystitis with tranexamic acid, at this time there is insufficient published data to support this.

Surgery

Unfortunately, a small percentage of patients will present with life-threatening hemorrhagic cystitis that is refractory to conservative and non-operative measures. These patients can be successfully treated with urinary diversion and cystectomy, however, the associated morbidity with this procedure is high. Surgery is reserved for the management of severe complications that do not respond to medical management. Indications for surgery include the following:

• Ongoing gross hematuria that does not respond to bladder irrigations or that requires numerous transfusions
• Small, contracted bladder with incontinence or severe frequency
• Specific complications of radiation (eg, fistulas, hydronephrosis, strictures)

Surgical options for small-volume bladder include bladder augmentation, urinary diversion, and cystectomy.

Several case series have examined the use of cystectomy in patients who had previously failed less invasive therapies. One series identified 21 patients with hemorrhagic cystitis, 17 from radiation therapy, who underwent cystectomy ⁴⁵. In this series, 42% of patients experienced severe complications (defined as Clavien grade III–V) and the 90-day mortality rate was 16%. This study echoes the findings of a larger case series looking at surgical outcomes from men undergoing urinary diversion via cystectomy for multiple adverse effects of radiation, including hematuria ⁴⁶. In this series, 36% of patients experienced Clavian III or greater complications, including 15% who required a second operation, and death in 4.5% of patients within the first 90 days. These rates of complications outpace the comparable rates in patients undergoing radical cystectomy for bladder cancer. Both authors attributed this to baseline fragility and comorbidities in this patient population exacerbated with the challenge of operating in a previously radiated field.

Small case studies have evaluated the use of urinary diversion alone in those who may not tolerate a cystectomy, either through cutaneous ureterostomy ⁴⁷ or bilateral nephrostomy tubes ⁴⁸. Although both studies were quite small, they showed improvement in hematuria using urinary diversion alone; this may be a beneficial surgical alternative in patients for whom cystectomy is not a viable option. Caution should be advised, as long-term followup in urinary diversion without cystectomy for benign conditions has shown a high rate of complications in the remaining bladder ⁴⁹.

Treatment of hemorrhagic cystitis

Hemorrhagic cystitis is a more serious complication of radiation cystitis. Cystoscopy is useful in the initial management, both diagnostically to rule out other pathology and for clot evacuation if bleeding is heavy. This can resolve symptoms in up to 61% of patients at initial presentation.

If bleeding is severe, bladder irrigation may be started either alone or in conjunction with hyperbaric therapy. Start continuous bladder irrigation alone first. If this is not successful, try bladder instillation. In order of increasing toxicity, these agents include 1% alum, aminocaproic acid (Amicar), and 1-10% formalin ⁵⁰. Other options are oral pentosan polysulfate sodium, Hyperbaric Oxygen Therapy, and oral estrogens ⁵¹. If symptoms persist, however, cystoscopic intervention is rarely successful ⁵².

Surgical options for hemorrhagic cystitis include the following:

• Cystoscopy and fulguration
• Percutaneous nephrostomy tube insertions
• Internal iliac artery embolization
• Surgical diversion
• Cystectomy

Cystectomy for hemorrhagic cystitis is associated with high rates of perioperative complications and mortality. It should be used only after more conservative approaches have been attempted ⁵³.

Refractory and life-threatening hematuria

Transarterial embolization

Advances in interventional radiology have allowed for accurate selective and super-selective transarterial embolizations (TAE) that provide clinicians with management alternatives to more radical surgical procedures in patients with persistent or life-threatening hematuria. The benefit of transarterial embolization is its safety and tolerability in comparison to more aggressive surgical procedures in the frail and elderly patients, who make up a significant proportion of patients with radiation cystitis. However, these procedures are not without their own risks and side effects.

Unfortunately, many of the studies on transarterial embolization for hematuria include urological bleeding of multiple etiologies and do not discriminate between blood loss from bladder or prostatic origins. In a case series of 44 patients looking at the role of transarterial embolization in the management of intractable hematuria hemorrhage of oncological origin, Liguori et al found that the majority of patients (82%) experienced an initial resolution of hematuria ⁵⁴. The ability to perform selective and superselective transarterial embolization has reduced the risk of ischemic-related side effects. Historical studies have demonstrated ischemic-mediated side effects in as high as 65% in patients undergoing internal iliac artery embolization ⁵⁵. Although most of these are transient post-embolization syndrome, they also include more serious complications, such as bladder necrosis and, in rare cases, Brown-Sequard syndrome. Comparable modern series published in the last decade quote minor and self-resolving complication rates from 9–31%, with a technical success rate of 88–100% ⁵⁶.

Formalin

Intravesical formalin was first described in the treatment of bladder hemorrhage in the late 1960s, and was soon assessed in a radiation cystitis cohort. The proposed mechanism involved capillary occlusion and protein fixation at the urothelium level ⁵⁷. Due to pain with administration, it must administered in an operating room setting with either a general or spinal anesthetic. While its rapid onset of action is appealing, its use is somewhat controversial because of its high morbidity, which appears to be proportional to the concentration of formalin used ⁵⁸.

The largest review of the efficacy of formalin instillation to treat hemorrhagic cystitis of multiple etiologies was a systematic review of retrospective case series published in 1989 ⁵⁹. The article included 235 patients stratified into three groups by the concentration of formalin instilled (10% vs. 3–6% vs. 1–2%). The complete response rates were 88%, 78%, and 71%, respectively. One benefit of formalin instillations was that complete response was typically achieved within 48 hours of a single instillation. Major complications were typically associated with refluxing into the upper urinary tract and consisted of ureteric stricture function, ureteropelvic junction and uretrovesical junction obstruction requiring urinary diversion, decreased bladder capacity, and vesicular fistulas. The mortality rates for 10% and 4–6% formalin instillation were recorded at 5.7% and 2.2%, respectively. No mortalities occurred in the 21 patients treated with 1–2% concentration.

Several other studies were completed that found formalin to be associated with a high treatment efficacy, but with potentially severe complications. In a study of 35 patient with radiation cystitis post-cervical radiation, 89% were found to have complete response after a single instillations; however, 31% had major complications ⁶⁰. One contemporary study investigated eight patients treated with formalin instillations after less invasive treatments had failed. In this study, each patient had a preoperative cystogram to assess for perforation or vesicoureteral reflux, and if any reflux was suspected, Fogarty catheters were used to obstruct the ureter ⁵⁷. Formalin concentration ranged from 1–4% and contact time was kept to 10–15 minutes. The complete resolution rate was 75% and only one patient had major complications necessitating intensive care unit admission. A detailed description of the procedure can be found within this article for clinicians unfamiliar with this treatment option.

Procedural variations for decreasing the morbidity associated with formalin instillations have been proposed, from decreasing formalin concentration to alternative methods of formalin delivery. A small, prospective study compared intravesical instillation of 4% formalin in 11 patients to endoscopic placement of formalin soaked pledgets ⁶¹. Success rate was similar (82% and 75%, respectively), however the intravesicle instillation group suffered from four major complications, whereas the pledget group suffered only minor side effects. The differences were not statistically significant and while a comparable method was described in two individual case studies ⁶², follow-up with further larger or prospective studies is lacking.

Radiation cystitis prognosis

Acute symptoms of radiation injury to the bladder are self-limiting and generally respond to symptomatic therapy, such as anticholinergic medications and analgesics. Severe complications of radiation injuries are difficult to manage because they tend to be chronic or recurrent and are occasionally refractory to therapy. Proper interpretation of treatment outcome is limited by few follow-up studies and the small number of patients reported in these studies.

The available follow-up studies performed with various treatment regimens demonstrate that although all have some effectiveness, no single modality is superior. They also show the recurrent nature of radiation complications of the bladder. Complications of radiation cystitis include hemorrhagic cystitis (3%-5%), vesical fistula (2%), and bladder neck contracture (3%-5%). Neoplasia and contracted bladder can also occur but are rare.

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