Practical Applications of Intravesical Chemotherapy and Immunotherapy in High-risk Patients with Superficial Bladder Cancer
Section snippets
Initial steps: adequate resection and perioperative cytotoxic chemotherapy
Chemotherapy and immunotherapy have the capacity to ablate small (<1.5 cm) residual tumors; however, recurrence rates are never as good as when therapy is applied in the prophylactic (no visible disease remaining) setting [2]. It is mandatory that as complete a resection as possible be performed before starting intravesical therapy. In some cases, this may mean additional sessions to remove tumor completely and achieve adequate staging information. With bulky or multifocal high-risk tumors,
Choosing a post–transurethral resection regimen for previously untreated patients
Although one-dose perioperative chemotherapy is a vital first step in decreasing tumor recurrence, fully two thirds of patients with multifocal tumors will still relapse. A sequential regimen of repetitive intravesical therapy can provide additional benefit. The choice of whether this should be a chemotherapy- or immunotherapy-based program is determined not only by personal preference but also by a careful assessment of the risk-benefit ratio for the agent in a particular patient. Chemotherapy
Maintenance chemotherapy
The use of additional treatments of intravesical chemotherapy after completion of the induction cycle at a time when the patient is already in complete clinical remission is known as “maintenance” therapy. The rationale for maintenance therapy is to prevent the emergence of new cancers from a diseased premalignant urothelium or to eradicate small clinically undetectable nests of residual cancer. The most common regimen involves monthly therapy, usually for at least a year, but variations of
Intravesical immunotherapy
Based on an absolute superiority in activity coupled with an increased familiarity and acceptance of its side effects, BCG has become the most popular choice for intravesical therapy in North America by an almost 2:1 majority. Interestingly, Europeans do not share this enthusiasm for BCG and use it only about one-third of the time. For low-to-intermediate risk cases of superficial bladder cancer, primary chemotherapy and BCG remain appropriate options; however, for high-risk cases, there is
Optimized administration of bacillus Calmette-Guérin
As is true for intravesical chemotherapy, many details of BCG administration have not been subjected to scientific rigor; rather, they have been derived from empiric observations. At least 7 to 14 days should elapse after the TUR before beginning BCG. Earlier administration has been associated with BCG sepsis. Many clinicians choose to wait 3 to 4 weeks or longer until all postoperative bleeding is over. A full induction cycle usually consists of six weekly treatments, but 8- and 12-week
What to do when treatment fails
Despite the strides made with intravesical chemotherapy and immunotherapy, most patients will eventually have a recurrence of disease. For intermediate-and high-risk patients treated with chemotherapy, the answer is simple—try BCG next. For BCG failures, the problem is more complicated, because salvage chemotherapy with traditional agents rarely achieves a greater than 20% 3-year disease-free rate [52]. Because a second course of BCG still provides between a 30% to 50% response, it is probably
Role of interferon, alone and combined with bacillus Calmette-Guérin
Interferons are natural glycoproteins that mediate host immune responses such as the stimulation of phagocytes, cytokine release, enhanced natural killer cell activity, and activation of T and B lymphocytes. Of all the interferons, IFN-α has been the best studied as an intravesical treatment agent [58]. When used by itself, IFN-α is well tolerated, causing minimal cystitis and only occasional low-grade fevers or flulike symptoms [59]. Its efficacy is clearly dose dependent, with minimal
Emerging technologies
Although not yet readily available to urologic practitioners in North America, two device technologies developed in Europe that facilitate drug delivery are showing great promise for primary and salvage therapy. Local hyperthermia using a specially designed microwave antennae Foley catheter in conjunction with concomitant MMC therapy (chemothermotherapy) has demonstrated encouraging results in ablating large tumor burdens as well as preventing recurrence after TUR of bladder tumor [78], [79].
Summary
The following steps are practical in the treatment of intermediate-to-high risk patients with superficial bladder cancer:
Resect all visible tumor at the time of first TUR of bladder tumor. Strongly consider re-resection, especially for high-risk, large, multifocal, stage T1 tumors.
Apply one dose of cytotoxic chemotherapy perioperatively within 6 hours of TUR (ideally immediately).
Once histopathology is available, consider intravesical induction chemotherapy for intermediate-risk patients and
References (85)
- et al.
Primary superficial bladder cancer risk groups according to progression, mortality and recurrence
J Urol
(2000) - et al.
Up-front intravesical chemotherapy for low stage, low grade recurrent bladder cancer
J Urol
(1996) - et al.
Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder
J Urol
(1991) The value of a second transurethral resection in evaluating patients with bladder tumors
J Urol
(1999)- et al.
A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials
J Urol
(2004) - et al.
FinnBladder Group: factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma
Eur Urol
(2002) - et al.
Finnbladder Group. Perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter study—FinnBladder III long-term results
J Urol
(2002) Complications of bacillus Calmette-Guerin immunotherapy
Urol Clin North Am
(1992)- et al.
European Association of Urology (EAU) Working Group on Oncological Urology: guidelines on bladder cancer
Eur Urol
(2002) - et al.
Bladder cancer clinical guidelines panel summary report on the management of nonmuscle invasive bladder cancer (stages Ta, T1 and TIS): the American Urological Association
J Urol
(1999)
Effect of prophylactic treatment with intravesical epirubicin on recurrence of superficial bladder cancer—the 6th Trial of the Japanese Urological Cancer Research Group (JUCRG): a randomized trial of intravesical epirubicin at dose of 20 mg/40 mL, 30 mg/40 mL, 40 mg/40 mL
Eur Urol
Pharmacokinetics of intravesical doxorubicin in superficial bladder cancer patients
J Urol
Intravesical chemotherapy with epirubicin: a dose response study
J Urol
Complications of intravesical chemotherapy
Urol Clin North Am
Natural history and treatment of low and high risk superficial bladder tumors
J Urol
Comparison of different schedules of cytostatic intravesical instillations in patients with superficial bladder carcinoma: final evaluation of a prospective multicenter study with 419 patients
J Urol
A randomized controlled trial of short-term versus long-term prophylactic intravesical instillation chemotherapy for recurrence after transurethral resection of Ta/T1 transitional cell carcinoma of the bladder
J Urol
Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials
J Clin Epidemiol
Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. European Organization for Research and Treatment of Cancer Genitourinary Group
J Urol
Bladder carcinoma in situ in 2003: state of the art
Eur Urol
Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity
J Urol
Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials
J Urol
Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression
Urology
Intravesical versus intravesical plus intradermal bacillus Calmette-Guerin: a prospective randomized study in patients with recurrent superficial bladder tumors
J Urol
Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results
J Urol
Five-year results of a phase II study with low-dose bacille Calmette-Guerin therapy in high risk superficial bladder cancer
Urology
Low dose Pasteur bacillus Calmette-Guerin regimen in stage T1, grade 3 bladder cancer therapy
J Urol
A low dose bacillus Calmette-Guerin regimen in superficial bladder cancer therapy: is it effective?
J Urol
Dose-response of bacillus Calmette-Guerin in the treatment of superficial bladder cancer
J Urol
Single course versus maintenance bacillus Calmette-Guerin therapy for superficial bladder tumors: a prospective, randomized trial
J Urol
Maintenance BCG immunotherapy in recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma: a randomized Southwest Oncology Group study
J Urol
Tolerability of bacille Calmette-Guerin maintenance therapy for superficial bladder cancer
Urology
Maintenance bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial
Eur Urol
5-Year follow-up of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma: Swedish-Norwegian Bladder Cancer Study Group
J Urol
Long-term results of intravesical bacillus Calmette-Guerin therapy for stage T1 superficial bladder cancer
Urology
Intravesical bacillus Calmette-Guerin in the treatment of superficial transitional cell carcinoma of the bladder
J Urol
Superficial bladder cancer: progression and recurrence
J Urol
Prognostic parameters in superficial bladder cancer: an analysis of 315 cases
J Urol
Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer
J Urol
Superficial bladder cancer: the role of interferon-alpha
J Urol
Results at 43 months' follow-up of a double-blind, randomized, prospective clinical trial using intravesical interferon alpha-2b in the prophylaxis of stage pT1 transitional cell carcinoma of the bladder
Urology
Intravesical immunoprophylaxis in recurrent superficial bladder cancer (stage T1): multicenter trial comparing bacille Calmette-Guerin and interferon-alpha
Urology
Cited by (31)
Management of High-grade, Nonmuscle Invasive Urothelial Carcinoma in a Prepubertal Patient With TURBT and Intravesical BCG
2019, UrologyCitation Excerpt :High-risk adults, including newly diagnosed CIS, high-grade T1, or high-risk Ta UC, should undergo a 6-week induction course of BCG after complete resection. In complete responders, maintenance BCG is recommended for 3 years, as tolerated.5,6 There is a 30% absolute advantage for disease recurrence in those treated with intravesical BCG compared to transurethral resection alone and a 27% reduction in disease progression in patients who receive maintenance therapy.7,8
Immunotherapy
2018, Bladder CancerImmunotherapy: Bacille Calmette-Guérin
2017, Bladder CancerPerioperative Chemotherapy. When to Use It, What to Use, and Why.
2013, Urologic Clinics of North AmericaCitation Excerpt :The catheter may then be removed and discarded in a biohazard container. Gloves should be worn at all times when handling this agent.54 A 2004 meta-analysis of 7 randomized trials22,23,26,38,55–57 compared a single perioperative instillation of intravesical chemotherapy following TURBT versus TURBT alone in patients with Ta or T1 bladder cancer.50
Benign Diseases of the Bladder
2008, Surgical Pathology ClinicsCitation Excerpt :Granulomatous cystitis comprises a group of entities characterized by granulomatous inflammation of the bladder with or without the presence of giant cells, which may occur at any age. Intravesical BCG, an attenuated form of Mycobacterium bovis used to treat superficial urothelial carcinomas, is one of the most oft-cited causes of this entity in developed nations, and prominent granulomatous inflammation has been reported in 60% to 80% of patients.76 Other causes of granulomatous cystitis include X-linked chronic granulomatous disease, sarcoidosis, and surgical injury, which induces granulomatous cystitis in as many as 14% of patients who have multiple surgeries.77–79
Predictors of Intravesical Therapy for Nonmuscle Invasive Bladder Cancer: Results From the Surveillance, Epidemiology and End Results Program 2003 Patterns of Care Project
2008, Journal of UrologyCitation Excerpt :Furthermore, it is worrisome that only 31% of patients with CIS in the absence of concomitant papillary lesions received intravesical treatment. Bladder CIS treated with transurethral resection alone is associated with a 60% to 80% progression rate to invasive disease within 5 years.11 Intravesical BCG has clearly been shown to delay recurrence and progression in this setting.12