Immunotherapy for non-muscle-invasive bladder cancer: from the origins of BCG to novel therapies

Supplies of intravesical Bacillus Calmette-Guérin (BCG), the first-line treatment for most intermediate- and high-risk non-muscle-invasive bladder cancers (NMIBC), have proven unreliable over the past decade. This review considers the evolution of BCG immunotherapy for NMIBC: from the discovery of the antitumour side effects of tuberculosis and subsequently the BCG vaccine, to recent advances in novel immunotherapeutic agents. We summarize the evidence for alternative options to standard intravesical BCG therapy regimens and describe the potential for immune response manipulating drugs in the treatment of NMIBC. These new agents, including immune checkpoint inhibitors, toll-like receptor agonists and recombinant viral vectors, may provide better options in the management of NMIBC in the future.

Checkpoint inhibitors in BCG-unresponsive nonmuscle invasive bladder cancer: can they help spare the bladder?

Intravesical BCG therapy has been for years, the standard of care in nonmuscle-invasive bladder cancer. But upon recurrence/relapse, radical cystectomy is imposed, due to the paucity of other therapeutic options. Immunotherapy has been revolutionizing cancer treatment, and its indications continue to broaden. It has been approved for the treatment of advanced urothelial cancer of the bladder, mainly as a second-line therapy. Its activity is being studied in nonmuscle-invasive bladder cancer that is not responsive to BCG; we herein report the trials investigating these checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab and avelumab) in this particular setting.

Acute Hepatitis Induced by Intravesical BCG Therapy: A Rare but Serious Complication

Bacillus Calmette and Guérin (BCG), widely used as a vaccination to prevent tuberculosis, is also used as immunotherapy, by intrabladder instillation, to treat superficial bladder cancers and prevent recurrence. Complications following instillation of BCG are most often localized reactions, such as cystitis or hematuria. They can more rarely be generalized and potentially severe such as hepatitis, pneumopathies, aortitis, and localization to hematopoietic tissue. We have reported the observation of a 47-year-old patient followed up for a bladder tumor operated for transurethral resection of the bladder, then having benefited from an instillation of BCG therapy complicated by occurrence a week later of an acute hepatitis. The diagnostic time was 2 days, and the outcome was favorable with corticosteroid therapy.

Association Between Antibiotic Treatment and the Efficacy of Intravesical BCG Therapy in Patients With High-Risk Non-Muscle Invasive Bladder Cancer

ObjectiveTo investigate the association between antibiotic therapy and the efficacy of intravesical BCG therapy in patients with high-risk non-muscle invasive bladder cancer (NMIBC).MethodsThis study involved the retrospective review of medical records of patients who underwent transurethral resection of bladder tumors for high-risk NMIBC followed by intravesical BCG therapy between 2008 and 2017. Patients were categorized as none, short- (2-6 days), and long-course use (≥7 days) based on the duration of antibiotic treatment concurrent with or initiated ≤30 days before BCG therapy. Oncologic outcomes, including recurrence-free survival and progression-free survival, were analyzed.ResultsOf the 276 patients enrolled in the study, 162 (58.7%) had pathologic T1 disease and 206 (80.2%) had high-grade disease. Concurrently with or prior to BCG therapy, 114 patients had (41.3%) received short-course antibiotic therapy, and 96 (34.8%) patients had received long-course antibiotics. The 5-year recurrence-free survival (62.2% vs 26.9%; log rank, p <0.001) and progression-free survival (79.6% vs. 53.3%; log rank, p=0.001) rates were significantly higher in patients who did not receive antibiotic therapy than in those treated with long-course antibiotics. Multivariable analysis revealed that antibiotic treatment for more than 7 days was independently associated with increased risks of recurrence (hazard ratio [HR], 2.45; 95% confidence interval [CI], 1.49-4.05; p < 0.001) and progression (HR, 3.68; 95% CI, 1.65-8.22 p = 0.001).ConclusionLong-course antibiotic treatment concurrently with or prior to intravesical BCG adversely influenced disease recurrence and progression outcomes in patients with high-risk NMIBC. Careful use of antibiotics may be required to enhance the efficacy of intravesical BCG therapy. Further mechanistic and prospective studies are warranted.

Disease management in a patient diagnosed with COVID-19 disease during induction intravesical BCG therapy: A case report and review of the literature

Objective: To discuss the patient diagnosed with COVID-19 disease while receiving intravesical induction bacillus Calmette-Guérin (BCG) treatment for non-muscle-invasive bladder cancer, its management in the light of the literature. Patient and methods: A 52-year-old male patient, who received intravesical BCG treatment for high-grade pT1 papillary urothelial carcinoma, presented 12 h after taking the fourth dose of induction therapy 38.2° fever and chills. The patient’s reverse transcriptase-polymerase chain reaction test was positive, and Thorax CT imaging showed a few ground-glass pneumonic infiltrations in bilateral lung bases consistent with COVID-19 disease. Results: Although international urology associations have current recommendations regarding the pandemic process, only one study has made specific recommendations regarding the patient group diagnosed with COVID-19 while receiving intravesical BCG treatment. According to this recommendation, we interrupted our patient’s BCG treatment for 3 weeks and then completed the treatment for 6 weeks. A maintenance treatment not exceeding 1 year was planned. Conclusion: This group of patients’ recommendation is to delay BCG therapy for at least 3 weeks after initial symptoms to allow for complete recovery. Although the administration schedule varies, maintenance therapy is recommended for no more than 1 year.

Is there a role for urine cytology following BCG therapy for non-muscle-invasive bladder cancer (NMIBC)?

404 Background: Voided urine cytology has been used as an adjunct in the diagnosis of non-muscle invasive bladder cancer (NMIBC), with a sensitivity and specificity ranging between 13-75% and 76-100% respectively. There is limited data on the accuracy and utility of cytology following BCG therapy. We reviewed the results of cytology in patients undergoing induction and maintenance BCG immunotherapy in our institution. Methods: Newly diagnosed patients who had received induction and maintenance intravesical BCG therapy from 2004 - 2019 were identified from a prospective database and their outcomes reviewed retrospectively. Histopathology results of biopsies / resected specimens and voided urine cytology results were examined for 273 patients. Results: A total of 2567 cytology results and 638 biopsy results were recorded. The average age was 73.2 years and median number of BCG treatments was four (induction followed by three maintenance courses). Median follow up was 38 months. 94 patients (34.4%) had recurrence following BCG therapy. Of those 33 patients (12.1%) had progression to muscle invasive disease. The number of cytology samples per patient after BCG therapy ranged from 1-23 (median 7), with several patients having repeated, potentially unnecessary negative urine cytology. Overall accuracy of cytology (n = 526) was sensitivity 44.2%, specificity 84.7%, PPV 38.9%, NPV 87.3%. Patients that had an erythematous bladder or red patch at flexible cystoscopy underwent subgroup analysis; this gave a very high NPV of 95.9%, with additional sensitivity being 65.5%, specificity 85.9% and PPV 33.3%. Number of positive cytology results (Chi2 = 44.30, P = 0.002), any positive cytology (Chi2 = 27.94, P < 0.001) and positive cytology after induction BCG therapy (Chi2 = 30.381, P < 0.001) were all strongly associated with recurrence. Conclusions: Positive urine cytology in patients undergoing intravesical BCG therapy predicts increased risk of recurrence and has good specificity. We would recommend using voided urine cytology in patients who have an erythematous bladder or red patch at flexible cystoscopy. If the cytology is positive then proceed to biopsy, however, if it is negative continue with surveillance. [Table: see text]

Novel and emerging approaches in the management of non-muscle invasive urothelial carcinoma

Non-muscle invasive bladder cancer (NMIBC) has traditionally been managed with transurethral resection followed by intravesical chemotherapy and/or bacillus Calmette–Guerin (BCG) in a risk-adapted manner. These tumors commonly recur and can progress potentially to lethal muscle invasive disease. A major unmet need in the field of NMIBC is bladder preserving therapy for recurrent high-grade NMIBC after adequate intravesical BCG therapy. The current gold standard treatment for these BCG-unresponsive patients is radical cystectomy, which is associated with considerable morbidity and mortality, particularly in older and frailer patients. It is therefore critical to provide alternative treatment options with acceptable oncological outcomes. In this review we explore novel bladder-sparing treatment options including combination intravesical therapy, enhanced instillation methods, immunotherapy, gene therapy, targeted therapy, photodynamic therapy and BCG variants across the spectrum of NMIBC disease states, ranging from low grade BCG-naïve patients through to high-grade BCG-unresponsive NMIBC.