Abstract
Intravesical therapy plays an integral role in the management of nonmuscle invasive bladder cancer. Therefore urologists should be familiar with the expected side effects and unexpected complications that can arise from intravesical therapy. Both intravesical bacille Calmette-Guérin (BCG) and chemotherapies commonly cause local, irritative voiding symptoms. These symptoms are often the reason for early cessation of treatment. Thus, it is important to properly counsel patients on these and other expected side effects. BCG therapy may result in more severe regional or systemic toxicity, such as BCG sepsis and granulomatous changes of various organs, whereas intravesical chemotherapies are generally less toxic systemically. Early recognition of severe complications is necessary to ensure patient recovery. This chapter reviews practical considerations when administering intravesical therapy, including an overview of side effects, management and prevention of complications, and contraindications to treatment.
Keywords
Bladder cancer, Nonmuscle invasive, Intravesical therapy, Bacille Calmette-Guérin, Intravesical chemotherapy, Complications, BCG sepsis, Transurethral resection
Key Points
- 1.
The local and systemic inflammatory toxicities of bacille Calmette-Guérin (BCG) are usually short-lived and can be managed symptomatically.
- 2.
Prevention of systemic absorption and infectious toxicity of BCG relies on healing of the bladder wall and avoidance of trauma at the time of instillation.
- 3.
Prompt recognition and treatment of BCG sepsis is essential, given its potential for mortality.
- 4.
Mitomycin C (MMC) is the least likely absorbed intravesical chemotherapeutic agent, given its molecular weight.
- 5.
Toxicity of MMC is usually related to irritation of the bladder and resolves with time. Nonetheless, instillation should be avoided in the setting of bladder perforation, large resection defects, or ureteral orifice resection.
- 6.
Although MMC is frequently given perioperatively, BCG should not be given until bladder wall healing is achieved following transurethral resection.
- 7.
Valrubicin and gemcitabine are newer agents with efficacy in BCG-refractory disease and mild toxicity profiles primarily limited to local, irritative symptoms.
Nearly 80% of newly diagnosed bladder cancers represent nonmuscle invasive urothelial carcinoma (i.e., stage Ta, stage T1, or carcinoma in situ [CIS]). Numerous intravesical agents may be used in the management of these cancers. Thus, specific knowledge of the toxicity of these agents is imperative for the practicing urologist.
Intravesical Immunotherapy
Bacille Calmette-Guérin
Bacille Calmette-Guérin (BCG) is used for patients with stage T1 tumors, CIS, or stage Ta tumors of high grade. Originally introduced for this indication by Morales and colleagues in 1976, BCG is now accepted as the most efficacious of the intravesical agents. Numerous studies demonstrate that the use of BCG reduces the risk of disease recurrence and progression.
BCG’s mechanism of action involves creating an inflammatory reaction in the bladder by means of live, attenuated mycobacteria. For this reason, the rate of local side and systemic side effects is high. The primary cytokines released following intravesical BCG administration are interferon-γ (IFN-γ) and interleukin 2 (IL-2); therefore, many of the systemic side effects noted with BCG are similar to those seen with the systemic administration of cytokines. The primary cytokine-related side effects of BCG often do not occur until the third or fourth instillation, a finding suggesting cumulative cytokine release with increasing exposure to the antigen.
Traditionally, BCG was given in 6 weekly instillations, although numerous studies indicate a significant benefit from maintenance therapy as opposed to induction therapy alone. The largest of these studies was the Southwest Oncology Group (SWOG) trial, which randomized 550 patients with recurrent Ta, T1, or CIS to receive either induction alone or induction and maintenance using 3-week treatments given at 3, 6, 12, 18, 30, and 36 months. Median time to disease recurrence was 35.7 months in the group without maintenance and 76.8 months in the maintenance group. At 5 years, the recurrence-free rate was 41% and 60%, respectively. Maintenance therapy, however, was not well tolerated; only 16% of the 243 patients completed all eight scheduled maintenance courses over 3 years.
Low-dose BCG was proposed as a means of decreasing toxicity and improving tolerance. A large randomized trial compared 500 patients treated with a BCG dose of either 27 mg (1/3 dose) or 81 mg and found no statistically significant difference in recurrence or progression between the two groups. The investigators reported a significant reduction in toxicity in the low-dose group. A subsequent study from the same group demonstrated that BCG 27 mg (1/3 dose) is superior to BCG 13.5 mg (1/6 dose) with regards to disease recurrence and equivalent with regards to side effects.
A shorter duration of maintenance therapy has been suggested as another approach to reduce BCG toxicity. A noninferiority, randomized study of 1355 patients compared 1/3-dose BCG with full-dose BCG and 1 year of maintenance with 3 years of maintenance therapy using a primary outcome of disease recurrence. One-third–dose BCG was not found to be inferior to full-dose BCG. In high-risk patients (i.e., T1 or grade 3), 3 years of maintenance with full-dose BCG reduced disease recurrence as compared to 1 year of maintenance with full-dose BCG, but there was no difference in disease progression or survival. This benefit from 2 additional years of maintenance with full-dose BCG was not observed in intermediate-risk patients. There was no significant difference in toxicity by either reducing the dose or the duration of maintenance.
Numerous strains of BCG are widely used: TICE, Connaught, RIVM, Armand Frappier, Pasteur, and Tokyo. In a large meta-analysis, Lamm and colleagues found no difference among the different strains in terms of clinical efficacy or side effects. Other studies have suggested that efficacy varies with strain, but there is currently insufficient evidence for specific recommendations.
Overview of Complications
Although BCG is generally well tolerated, every urologist should be familiar with the expected and unexpected adverse effects. Soloway and associates reviewed 234 patients referred from community urologists and found significant numbers of patients treated for Ta G1 disease, a pathologic stage and grade in which one must seriously consider whether the side effects of BCG outweigh the small benefit in treatment of typically indolent disease.
A distinction should be made between expected side effects and true complications of BCG therapy ( Table 22.1 ). Local and systemic toxicities can be divided into immune-mediated or infection-mediated complications. Local toxicities are generally treatable and unavoidable symptoms. Some degree of local toxicity is experienced by virtually all patients, although the reported incidence in contemporary series ranged from 27% to 90% depending on sample size, dose and regimen, and definition of local toxicity. Although many investigators believe that a strong correlation exists between BCG toxicity and efficacy, this link has never been proven in clinical trials.
| Study (year) | No. Patients | Induction Dose | Maintenance Dose | Irritative Voiding Symptoms | Fever | Sepsis | Death |
|---|---|---|---|---|---|---|---|
| Pagano et al (1991) | 126 | 75 mg Pasteur, 6 wk | Monthly × 1 yr, every 4 mo × 1 yr | 30% | 17% | 0% | 0% |
| Lamm et al (1992) | 2602 | 50 mg, 6 wk | 90% | 2.9% | 0.4% | 0% | |
| Witjes et al (1993) | 140 | TICE 5 × 108 CFU/50 mL, 6 wk | 3 and 6 mo, 6 weekly treatments if recurrence | 30% | 2% | 0.71% | 0% |
| Martinez- et al (1990) | 252 | Connaught, 81 mg/50 mL, 6 wk | 6 instillations every 2 wk | 71% | 2% | 0% | 0% |
| 248 | Connaught, 27 mg/50 mL, 6 wk | 62% | 2% | 0% | 0% | ||
| Vegt et al (1997) | 290 | 50 mg, 6 wk | 3 weekly instillations at 3, 6, 12, 18, 24, 30, 36 mo | 53% | 11% | 0% | 0% |
| Bassi et al (1999) | 126 | Pasteur 75 mg | Monthly × 1 yr, every 4 mo × 1 yr | 27% | 17% | 0% | 0% |
| Iori et al (2002) | 41 | TICE 5 × 108 CFU/50 mL | Monthly × 11, every 3 mo × 4, every 6 mo × 6 | 68% | 2.4% | 0% | 0% |
| Kolodziej et al (2002) | 102 | TICE 5 × 108 CFU/50 mL, 6 wk | 3 weekly instillations at 3, 6, 12, 18, 30, 36 mo | 84% | 13% | ? | 0% |
| Gontero et al (2013) | 57 | Connaught, 27 mg/50 mL, 6 wk | 3 weekly instillations at 3, 6, 12 mo | 36.8% | 17.5% | 0% | 0% |
| Brausi et al (2014) | 1316 | TICE 5 × 10 8 CFU/50 mL, 6 wk TICE 5 × 10 8 CFU/150 mL, 6 wk | 3 weekly instillations at 3, 6, 12 +/− 18, 24, 30, 36 mo | 63% | 8.1% | 0.3% | 0% |
Systemic complications are uncommon, and >95% of patients will tolerate the treatment well. In a review of 2400 cases, Lamm and colleagues found that fever >103°F was the most severe adverse event (2.9%). Other systemic complications include granulomatous changes, sepsis, pneumonitis, hepatitis, arthralgias, and cutaneous manifestations. Although major adverse reactions are unusual, it is important that the urologist recognize, diagnose, and treat these conditions early. When these complications are diagnosed and treated appropriately, virtually all patients recover from them with no long-term sequelae.
In an attempt to reduce side effects and improve tolerability, isoniazid (INH) has been tested as a prophylactic adjunctive treatment with BCG. A study by Vegt and associates did not show any reduction in local or systemic reactions when INH was used prophylactically. In addition to not providing any protection against reactions to BCG, INH was associated with a significantly higher risk of developing abnormal hepatic transaminase levels. More recently, ofloxacin was given in a randomized multicenter trial to 115 patients undergoing BCG treatment. Prophylactic ofloxacin was found to decrease the incidence of moderate-to-severe adverse events, which many investigators believe cause patients to discontinue treatment. No negative effect on efficacy was reported in the ofloxacin-treated group.
Specific Complications
We generally categorize the side effects of BCG as local, inflammatory, or infectious. Management and prevention of these side effects depend on the timing of BCG administration and the early recognition of symptoms.
Local Toxicity
The most commonly seen local toxicity of BCG is cystitis-like irritative voiding symptoms, reported in ≤90% of patients. Severe symptoms typically occur after the third instillation when lymphokine release causes the maximal inflammatory response. Consideration should always be given to secondary bacterial infection, and a negative urine culture should be obtained before further BCG administration. If a urinary tract infection (UTI) is present, it should be treated and BCG should be delayed until 1 week after resolution of the infection.
Most local symptoms subside within 2 to 3 days of administration, but in severe cases, symptoms can persist for several weeks after completion of therapy. Management should include local analgesics such as phenazopyridine and anticholinergics if severe bladder overactivity is noted. However, further study regarding anticholinergics is required, as a recent randomized study did not demonstrate improvement in urinary symptoms with oxybutynin. BCG dose reduction may be considered on follow-up administration, but unless the problem is severe, doses should not be withheld on the basis of local irritative symptoms alone. These patients may also benefit from treatment with quinolones, though it is unclear if quinolones will reduce further efficacy. Ofloxacin 200 mg given twice after each BCG instillation was found to reduce toxicity and improve compliance with BCG therapy. Antituberculosis therapy (e.g., isoniazid, rifampin) has not demonstrated efficacy in the prophylactic setting. We have generally avoided quinolones during BCG administration, and monitored urine cultures on a routine basis to determine the need for antibiotic therapy.
Gross hematuria occurs in 1–34% of patients receiving BCG. It is usually self-limiting and most commonly occurs after the second or third dose. Urine culture should be obtained. Further BCG administration should be delayed until resolution of hematuria. If hematuria does not resolve after 2 to 3 weeks of observation, repeat cystoscopy is indicated to exclude the possibility of recurrent tumor.
Inflammatory Toxicity
Flulike symptoms, such as low-grade fever <101.3°F, often accompany the irritative voiding symptoms. Malaise, myalgia, and low-grade fever typically last 24 to 48 hours. Treatment with acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) is typically successful. In many cases, we have used prophylactic acetaminophen administered at the time of BCG instillation if patients have previously demonstrated such toxicity upon administration. In our experience, the likelihood of inflammatory toxicity may increase with increasing exposure to BCG, and it is rare for patients to have substantial symptoms within the first few doses of induction. Over time, if administered as maintenance therapy, inflammatory toxicity may increase, and dose reduction can be an effective strategy when symptoms become severe. If no resolution is noted after 48 hours, or symptoms are severe and refractory to simple maneuvers, consideration should be given to antituberculosis therapy with two or more agents until symptoms resolve.
Infectious Toxicity
High fever (>102–103°F) or shaking chills suggests fever resulting from systemic absorption and warrants empiric treatment with antituberculosis therapy. Failure to treat or delay in diagnosis can result in a progression to sepsis and mortality.
Sepsis typically occurs in <4% of patients. In patients who develop BCG sepsis, therapy must be immediate and aggressive. More than 10 deaths have been attributed to BCG sepsis, and the rate is estimated to be 1 death for every 12,500 patients treated with intravesical BCG. The classic presentation is a patient with history of traumatic catheterization who presents with fever, chills, hypotension, and mental confusion. Respiratory failure, hepatomegaly, jaundice, leukopenia, and disseminated intravascular coagulopathy can occur. Although BCG sepsis generally occurs soon after instillation, a delayed onset several months after BCG therapy is possible. Results of culture are typically negative for mycobacteria, and treatment must be started based on clinical suspicion.
Management includes cessation of intravesical BCG, consultation with an infectious disease specialist, and administration of INH, rifampin, ethambutol, fluoroquinolones, and high-dose corticosteroids. Empiric coverage of gram-negative organisms and/or Enterococcus can also be considered. Lamm proposed that BCG sepsis is, in part, the result of a delayed-type hypersensitivity reaction, and for this reason the administration of 40 mg prednisolone may improve survival. Whereas corticosteroids and fluoroquinolones may be discontinued after the resolution of symptoms, antituberculosis agents should be continued for a minimum of 6 months. Addition of a fourth antituberculosis drug can be considered in severe cases. Of note, BCG strains are not sensitive to pyrazinamide. The use of cycloserine has previously been proposed by some investigators for systemic BCG absorption. Although the use of this agent has shown a survival advantage in mice, it appears to be ineffective against currently used BCG strains and thus is not recommended.
Prevention of Systemic Absorption
Numerous factors may contribute to the risk of systemic absorption. Most commonly, traumatic catheterization, a nonhealing resection site, and unrecognized UTI are the leading suspects.
During catheterization of a patient for BCG instillations, any difficulty or trauma should raise concern. At least seven reported deaths have resulted from systemic BCG infection after traumatic catheterization. At the time of instillation, atraumatic catheterization is essential. If traumatic catheterization does occur, BCG therapy should be withheld for 1 week. A history of significant urethral stricture may be a contraindication to BCG therapy. In these patients, the stricture disease should be treated definitively prior to initiating intravesical therapy.
On rare occasions, a patient can be treated with a catheter in place. Following catheterization, the BCG is instilled and the catheter is left capped for 2 to 3 hours, depending on the patient’s bladder capacity. Caution must be exercised to ensure that the patient does not have poor compliance or detrusor instability, which may result in high intravesical pressure and systemic absorption. Such individuals may not be appropriate candidates for BCG therapy if they also have poor bladder capacity. BCG should not be administered in the setting of known muscle-invasive or necrotic bladder cancer.
BCG instillation should be performed by gravity, not by pressurized instillation. Generally, a syringe with the piston removed can be attached to the catheter and used as a reservoir for gravity-driven instillation.
Following tumor resection, it is recommended to withhold BCG for 2 weeks. We have found an interval of 2 to 3 weeks with resolution of hematuria is usually sufficient to allow healing without affecting therapeutic outcome. In patients with a large resection bed, flexible cystoscopy can be used to ensure healing, and the presence of residual tumor, before BCG instillation. Gross hematuria or significant microscopic hematuria should have resolved before instillation. Periodic urine culture is useful to identify UTI. Symptoms alone may not be helpful for identification of UTI because most patients experience some irritative voiding symptoms.
Granulomatous Complications
Granulomatous prostatitis is reported to occur in 1–27% of patients receiving BCG therapy, depending to some degree on the treatment regimen. The true incidence of this complication is likely much higher and was found to be as high as 40% among patients undergoing biopsy in one study. Granulomatous prostatitis is usually discovered incidentally on digital rectal examination in patients with or without an elevated prostate-specific antigen (PSA) level. In the small percentage of patients who are symptomatic (6%), Lamm and associates noted that these patients usually present with acute prostatitis or urinary retention. Biopsy is needed to rule out cancer, and once the diagnosis is made, asymptomatic patients can be observed. Symptomatic disease warrants cessation of BCG instillations and treatment with INH 300 mg/day and rifampin 600 mg/day for 3 to 6 months and high-dose fluoroquinolones and corticosteroids until symptoms resolve.
It is wise to obtain a PSA level before BCG therapy. This test should be performed at a time distant from lower tract instrumentation. If test results are normal, PSA need not be measured until 1 year following BCG instillation. In individuals undergoing maintenance therapy, we determine the PSA level immediately before the 12-month maintenance dose. Prostate nodules and elevated PSA are common in men undergoing BCG therapy. Given the frequent instrumentation, rises in PSA level are difficult to interpret. We have found multiparametric prostate MRI to be invaluable in this setting as it often distinguishes between inflammation, BCG granuloma, or regions suspicious for prostate cancer. One may give a course of INH for 2 to 3 months to assess the cause of PSA elevation. If the BCG treatment was given in the remote past, the urologist should proceed directly to biopsy on the basis of PSA or abnormal exam.
More infrequently, granulomatous epididymo-orchitis or even granulomatous balanoposthitis can occur. Patients with granulomatous epididymo-orchitis generally present with local induration and pain. Local symptoms may be accompanied by fever or leukocytosis. A diagnosis of bacterial infection should be excluded, as epididymo-orchitis in the setting of BCG therapy is often caused by gram-negative bacteria. Treatment is with INH and rifampin for 3 to 6 months and fluoroquinolones and steroids until symptoms resolve. Some cases may proceed to abscess formation requiring orchiectomy for definitive treatment. Granulomatous balanitis can present with erythematous nodules on the glans and should be treated with antituberculosis therapy.
Granulomatous hepatitis and pneumonitis represent systemic infection and occur in <1% of patients treated with BCG. Granulomatous hepatitis presents with typical signs and symptoms of hepatitis, such as fever, jaundice, and anorexia. Granulomatous pneumonitis presents with general malaise, shortness of breath, and fever >101°F. One death has been reported from granulomatous hepatitis and BCG sepsis. A full fever workup that includes elevated liver enzymes and a chest radiograph or CT scan are needed to delineate the diagnosis. Liver biopsy is required to confirm the presence of granulomatous hepatitis. Hospitalization, fluid resuscitation, and acetaminophen are essential. INH and rifampin are given for 3 months with ethambutol added for severely ill patients. The incidence of hypersensitivity reaction from BCG is unclear, but investigators have reported that some granulomatous reactions result from an immune rather than an infectious process. Although no controlled studies have been conducted of steroid therapy in BCG-infected patients, preliminary data reveal that prednisolone (40 mg/day) may be added in unremitting conditions, as in the case of BCG sepsis.
Granulomatous reactions also occur in the bladder. Contracted bladder occurs in <1% of patients, but patients receiving maintenance therapy may be at higher risk, and some investigators have advocated use of prophylactic INH to decrease the likelihood of this complication. Management of contracted bladder consists of hydrodistention and withholding of BCG. If conservative measures fail, cystectomy may be required. Ureteral obstruction may occur secondary to edema or inflammation of the orifice and is reported in <0.3% of patients. CIS and vesicoureteral reflux are probably predisposing factors. This rare complication may require ureteral stenting or percutaneous drainage to relieve the obstruction.
Granulomatous reactions of the bone and bone marrow may rarely occur. Osteomyelitis of the vertebral bodies has been reported. Patients can present with back pain or even motor weakness. The presence of cytopenia should arouse suspicion of bone marrow involvement. Treatment is with antituberculosis therapy and cessation of BCG therapy.
Arthralgic Complications
Arthralgia and arthritis are some of the rare severe complications associated with BCG therapy. Joint involvement occurs in approximately 0.5% of cases. Arthritis usually occurs ≤2 weeks after the last instillation, whereas arthralgias can appear within a few days of instillation and become more severe with further instillations. Arthritis may occur within the complex of Reiter syndrome. The symptoms may resolve with NSAID treatment. If symptoms persist, administration of antituberculosis drugs and steroids should be considered.
Arthralgias with associated skin rash likely indicate an allergic reaction to BCG. Treatment begins with NSAIDs and antihistamines. Refractory or severe symptoms require discontinuation of BCG and use of INH, rifampin, quinolones, and steroids.
Rare Complications
Penile edema and meatal ulceration have been reported with and without lymph node enlargement. A 3-month course of INH and rifampin therapy should be given. Cutaneous complications of BCG therapy are rare, but penile edema and meatal ulceration suggest the possibility of local spillage. Other rare reported complications include nephrogenic adenoma, immune complex glomerulonephritis, choroiditis, cardiac toxicity, suppurative lymphadenitis, mycotic aneurysm, aortoduodenal fistula, lupus vulgaris, and musculoskeletal lesions.
Continuing Therapy and Maintenance
Patients experiencing mild local and systemic inflammatory side effects can be safely continued on an unmodified dose of BCG. In individuals experiencing severe local side effects or systemic toxicity lasting >48 hours, we recommend withholding the dose until symptoms have resolved and then resuming treatment with a lower dose of BCG (1/3, 1/6, 1/12, or 1/100 dilution) to reduce the severity of symptoms. Evidence suggests that 1/3 dilutions are the minimum effective dose in maintenance. In our practice, however, we have occasionally reduced the dose to 1/6 or 1/12, transiently, with later a attempt to increase the dose back to a 1/3 dose. In general, prophylactic use of INH is not indicated unless the clinician suspects systemic absorption of the organism. Prophylactic ofloxacin 200 mg given twice following each BCG instillation is a reasonable option to reduce side effects. We have always been concerned that quinolones have the potential to reduce efficacy given their cytotoxic effect on the BCG organism.
In patients with high fever or severe local symptoms, once the symptoms resolve, the clinician should rule out obvious reasons for systemic absorption such as traumatic catheterization, bladder wall ulceration, or timing in relation to transurethral resection. Individuals who have experienced severe systemic illness or sepsis should not receive further BCG therapy.
Numerous studies have shown that long-term maintenance therapy is associated with a poor rate of compliance, ranging from 16% to 65.5%. In comparison with nonmaintenance regimens, patients undergoing maintenance therapy clearly have a greater incidence of side effects, and compliance seems directly related to the duration and total number of instillations. Most treatment cessations are secondary to local or regional symptoms of irritation. Although low-grade fever is common and increases in incidence with successive maintenance doses, this complication has not been found to be associated with cessation of therapy. Recent evidence suggests that in patients without high-risk cancer, 1 year of maintenance therapy is effective and thus might be an option in patients with intolerable side effects. Alternatively, we have used a modified regimen of administration at 3, 6, 12, 18, 24, 36, 48, and 72 months. Anecdotally, this regimen has been better tolerated.
In follow-up, we have generally chosen to perform cystoscopy no sooner than 3 months following BCG administration, in part because of the high likelihood of ongoing bladder wall inflammation, but additionally because of the need for an adequate period to allow therapeutic efficacy, particularly in the setting of CIS. BCG inflammation can take on several appearances, but typically is demonstrated as a patch of raised, friable erythema, or bullous edema, in the dome of the bladder. Similar findings, located at the previous site of resection, are commonly observed as well. Use of cytology, and biopsy if cytology is abnormal, can differentiate apparent BCG inflammation from persistent urothelial cancer. In cases of normal cytology, deferral of maintenance BCG for 6 weeks with repeat inspection can be considered prior to biopsy.
Purified Protein Derivative Conversion
Routine purified protein derivative (PPD) skin testing prior to administering intravesical BCG is unnecessary, as most patients in the United States are at low risk for active tuberculosis infection. A positive PPD test without evidence of active disease is not a contraindication to intravesical BCG. PPD positivity may in fact be encouraging, as patients with prior immunity to BCG as demonstrated by a positive PPD may have improved recurrence-free survival without experiencing greater toxicity.
PPD conversion to a positive test result occurs in approximately 34% of patients previously treated with intravesical BCG and should not be considered a complication of BCG therapy. Although favorable responses to treatment have been shown to occur more frequently in patients with PPD conversion, this factor has not been shown to be a reliable indicator of either prognosis or tolerance of therapy.
Contraindications
Classic contraindications to BCG therapy include human immunodeficiency virus (HIV) infection, leukemia, lymphoma, organ transplantation, pregnancy, breast-feeding, active tuberculosis, and intractable UTIs. In severely immunocompromised patients, there is a theoretical concern for increased risk of systemic BCG toxicity. However, limited evidence has demonstrated efficacy and safety in some of these patient groups.
Yossepowitch and colleagues evaluated the use of BCG induction therapy in 24 “immunocompromised patients” with lymphoma, chronic obstructive pulmonary disease, or steroid therapy and found a response rate of 58% overall; only a single patient experienced a self-limited febrile illness (≤39.3°C for 48 hours after his third BCG cycle).
BCG therapy has been safely given in several small studies of patients with renal transplants. Some investigators utilized prophylactic antituberculosis drugs and adjusted immunosuppressive doses due to possible drug interactions. Herr and colleagues administered an induction course of BCG in 45 immunosuppressed patients, including those with organ transplants, cancer treated with chemotherapy, or corticosteroid use. Transplant patients experienced higher rates of treatment failure, recurrence, and progression. No patients in this cohort developed bacterial or BCG sepsis. Thus, they concluded that intravesical BCG is effective and safe in these immunocompromised patients. Caution should still be practiced when considering intravesical BCG in immunocompromised patients, as there is only preliminary evidence suggesting its safety. Severely immunocompromised patients should not undergo BCG therapy.
There are scarce data regarding the use of intravesical BCG in patients with HIV. Only two such patients were identified, one of whom with a CD4+ lymphocyte count of 10/mm 3 developed interstitial pneumonitis following BCG therapy. In patients with HIV well-controlled with medications, BCG therapy might be safe but is yet unproven.
No contraindication exists for BCG therapy in patients with valvular heart disease, prosthetic heart valves, or orthopedic hardware. Appropriate antibiotic prophylaxis for bacterial endocarditis should be administered in these patients before urethral instrumentation is undertaken but is not necessary for simple urethral catheterization during BCG instillation.
Another area of debate is transmission of BCG by sexual intercourse. Even though no cases of sexual transmission have been reported, use of a condom is generally advised during sexual intercourse for 1 week after BCG therapy.
BCG may be given to patients with vesicoureteral reflux without significant risk of complication. Some investigators have advocated resection of the ureteral orifices to induce reflux before BCG therapy to increase the proportion of urothelium in contact with BCG. Only one case of necrotic pyelonephritis has been reported. When patients do develop severe febrile reactions to BCG, consideration should be given to BCG pyelonephritis or renal abscess.
Interferons
Interferons (IFNs) are proteins with antiviral, antiproliferative, and immunomodulatory properties. Three classes of IFNs are recognized: IFN-α, IFN-β, and IFN-γ derive from leukocytes, fibroblasts, and lymphocytes, respectively. IFNs stimulate macrophages for antigen presentation, promote cytokine release, enhance natural killer cell activity, and indirectly activate T and B lymphocytes.
The best studied IFN is IFN-α. When it is used alone, this agent is well tolerated, with minimal local inflammatory effects or low-grade fever. Efficacy depends on dose (range, 10 million to 100 million U). IFN-α is less effective and more expensive than BCG, and therefore its primary use is in salvage intravesical therapy for BCG-refractory tumors. In patients with CIS and BCG treatment failure, the complete response to IFN-α is 15–20% at 1 year, with a durable response rate of 12% by 2 to 3 years.
Complications
Most side effects of IFN are the result of the systemic inflammatory response generated by lymphokine release. Acute IFN toxicity consists of flulike symptoms, which occur in 0–27% of patients and include chills, fever, headache, malaise, and myalgia. Chronic toxicities include fatigue, weight loss, and anemia. Some patients (0–10%) develop local cystitis and hematuria. Most adverse events resolve with expectant management within 24 to 48 hours of onset or on discontinuation of therapy. Acetaminophen can be used as a supportive agent to reduce fever and myalgia. Although treatment is generally symptomatic, dose reduction can aid in the completion of therapy.
O’Donnell and colleagues conducted a phase II randomized trial comparing IFN alfa-2b with BCG and found systemic side effects in 5.3% of patients. The use of low-dose BCG showed a trend toward decreased severe inflammatory and infectious events.
Although most toxicities associated with intravesical IFN are mild, transient, and completely reversible on discontinuation of therapy, these symptoms can occasionally interfere with patient compliance and completion of therapy. Dose reduction (25 or 10 million U, if necessary) offers a potential means of continuing therapy.
Intravesical Chemotherapy
Intravesical chemotherapy is an important class of therapeutics for treatment of Ta and T1 bladder carcinoma. The most commonly used drugs are mitomycin C (MMC), epirubicin, doxorubicin, valrubicin, and gemcitabine. Intravesical chemotherapy can usually be administered immediately following transurethral resection. Given the high molecular weight of chemotherapeutic drugs, the risk of absorption is low; consequently, systemic toxicity is of smaller concern than with BCG. Local symptoms due to irritation are most prevalent, and few side effects are immunologically mediated. As such, the side effects of individual agents are commonly related to the drug itself. Furthermore, the use of intravesical chemotherapy precludes the risk of sepsis and death associated with BCG therapy.
Mitomycin C
Mitomycin C is an antibiotic chemotherapeutic alkylating agent that acts by inhibiting DNA synthesis. Because of its high molecular weight, MMC is not easily absorbed and has a lower incidence of systemic reactions. This agent has been used in 20- to 60-mg doses for 8 weeks, although the usual dose is 40 mg in 40 mL of saline or water intravesically for 8 weeks followed by monthly maintenance therapy for 1 year in most studies. Table 22.2 summarizes the different schedules of intravesical MMC therapy and their associated side effects.
| Study (year) | No. Patients | Induction Dose | Dose Frequency | Chemical Cystitis | Bladder Capacity Reduction | Contact Dermatitis | Leukopenia | Thrombocytopenia |
|---|---|---|---|---|---|---|---|---|
| Nissenkorn et al (1981) | 29 | 8 × 40 mg/mL | Weekly induction; every | 3 (10%) | None | 3 (10%) | None | None |
| Prout et al (1982) | 28 | 8 × 40 mg/mL | Weekly induction | 9 (32%) | None | None | None | None |
| Issell et al (1984) | 60 | 8 × 40 mg/mL | Weekly induction | 33% | None | 7 (12%) | 3 (5%) | 1 (2%) |
| Huland et al (1990) | 209 | 20 mg/20 mL | Every 4 wk × 1 yr; every 3 mo × 1 yr | 25% | None | None | None | None |
| 96 | 20 mg/20 mL | Weekly × 8 wk; Monthly × 3 yr | 12% | None | None | None | None | |
| 75 | 20 mg/20 mL | Weekly × 20 wk | 18% | None | None | None | None | |
| Eijsten et al (1990) | 75 | 2 × 20 mg or 30 mg; 2 doses in first wk | Every 2 wk × 6 mo; Monthly × 6 mo; every 2 mo × 1 yr | None | 17 (23%) | None | None | None |
| Rintala et al (1996) | 93 | 5 × 20–40 mg | Weekly induction; every mo × 1 yr; every 3 mo × 1 yr | 3 (3%) | None | 3 (3%) | None | None |
| Bohle et al (2003) | 776 | Meta-analysis | Meta-analysis | 39.2% | NA | NA | NA | NA |
| Friedrich et al (2007) | 179 | 20 mg | Weekly × 6 wk | 11.6% | None | None | None | None |
| 153 | 20 mg | Weekly × 6 wk; monthly × 3 yr | 20.5% | None | None | None | None | |
| Filson et al (2014) | 116 | 40 mg/40 mL | Single perioperative dose | 27.6% | None | None | None | None |
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