BCG remains the most important vaccine for tuberculosis 100 years after its first use, and over the past 4 decades it has become the most widely accepted, effective drug used in the treatment of ...aggressive localized bladder cancer. This review chronicles the narrow path that led to approval and world-wide acceptance of BCG immunotherapy for bladder cancer while immunotherapy trials in other malignancies were abandoned. Six intravesical instillations of 5x10^8 CFU of BCG weekly after bladder tumor resection, first reported in 1976, is superior to resection alone and resection plus intravesical chemotherapy. Maintenance of effective immune stimulation is surprisingly difficult, but 3 weekly treatments 3, 6, and 12, 18, 24, 30 and 36 months after induction produces further significant reduction in tumor recurrence. This 3 week BCG maintenance schedule alone has reduced disease progression and mortality in multicenter randomized clinical trials. In the new age of immuno-oncology patients with many types of cancer now benefit from immunotherapy, but currently these modern agents are prohibitively expensive for most of the world. In contrast, the low cost and therefore low profitability of BCG has resulted in recurrent shortages that threaten both bladder cancer patients and children at risk for tuberculosis and other serious infections. Humanity has greatly benefited from early 20th century science that developed BCG and the benevolence of doctors Calmette and Guerin who put people over profit and widely shared cultures of the vaccine. The 21st century is bringing new immunotherapies and greatly expanding the types of malignancies that can be treated. Recombinant technology is expected to improve both the efficacy and production of BCG, hopefully expanding the availability of BCG and relieving the recurring supply shortage for both vaccination and cancer therapy.
To provide recommendations on appropriate clinical trial designs in non-muscle-invasive bladder cancer (NMIBC) based on current literature and expert consensus of the International Bladder Cancer ...Group.
We reviewed published trials, guidelines, meta-analyses, and reviews and provided recommendations on eligibility criteria, baseline evaluations, end points, study designs, comparators, clinically meaningful magnitude of effect, and sample size.
NMIBC trials must be designed to provide the most clinically relevant data for the specific risk category of interest (low, intermediate, or high). Specific eligibility criteria and baseline evaluations depend on the risk category being studied. For the population of patients for whom bacillus Calmette-Guérin (BCG) has failed, the type of failure (BCG unresponsive, refractory, relapsing, or intolerant) should be clearly defined to make comparisons across trials feasible. Single-arm designs may be relevant for the BCG-unresponsive population. Here, a clinically meaningful initial complete response rate (for carcinoma in situ) or recurrence-free rate (for papillary tumors) of at least 50% at 6 months, 30% at 12 months, and 25% at 18 months is recommended. For other risk levels, randomized superiority trial designs are recommended; noninferiority trials are to be used sparingly given the large sample size required. Placebo control is considered unethical for all intermediate- and high-risk strata; therefore, control arms should comprise the current guideline-recommended standard of care for the respective risk level. In general, trials should use time to recurrence or recurrence-free survival as the primary end point and time to progression, toxicity, disease-specific survival, and overall survival as potential secondary end points. Realistic efficacy thresholds should be set to ensure that novel therapies receive due review by regulatory bodies.
The International Bladder Cancer Group has developed formal recommendations regarding definitions, end points, and clinical trial designs for NMIBC to encourage uniformity among studies in this disease.
What's known on the subject? and What does the study add?
The administration of Bacillus Calmette‐Guérin (BCG) immunotherapy has become the standard of care for high‐grade non‐muscle invasive bladder ...cancer (NMIBC) and carcinoma in‐situ (CIS) in terms of prevention of recurrence and progression. While most agree on a 6 week induction cycle, various maintenance schedules (if any at all) have been implemented without a unifying consensus.
This review assesses the historical emergence of BCG immunotherapy, beginning with its discovery as a vaccinatin for tuberculosis to its effect on the host immune system and potential therapeutic benefits for various oncologic conditions. The data establishing BCG immunotherapy as the standard of care for high‐grade NMIBC and CIS over other bladder instillation modalities is presented in addition to the effect maintenance BCG therapy has on sustaining the immuno‐protective effect.
Bacillus Calmette‐Guérin (BCG) immunotherapy is currently the most effective treatment of non‐muscle invasive bladder cancer and one of the most successful applications of immunotherapy to the treatment of cancer.
This review summarises the history and development of BCG as a modern cancer treatment, appraises current optimal application of BCG immunotherapy in bladder cancer, discusses promising new therapies closely related to BCG, and briefly explores the possibility that BCG or related treatments may have an application in other urological malignancies.
BCG is a nonspecific stimulant to the reticuloendothelial system and induces a local inflammatory response with the infiltration of granulocytes followed by macrophages and lymphocytes, particularly helper T cells.
The initial BCG controlled trial showed a statistically significant reduction in tumour recurrence and found the advantage increased with duration of follow‐up. Similar results were reported in much higher risk patients in an independent concurrent study. Follow‐up suggested that a single 6‐week course of intravesical BCG provided long‐term protection (up to 10 years) from tumour recurrence and even reduced disease progression.
While induction BCG (six weekly instillations) reduced recurrence, progression and mortality at 10 years, this advantage was lost by 15 years, and patients remained at high risk for progression without the use of maintenance BCG.
In a meta‐analysis by the Cochrane group, induction BCG was found to be markedly superior to mitomycin C in high‐risk patients but not in low‐risk patients. Additionally, the National Comprehensive Cancer Network guidelines lists the use of intravesical BCG as preferred therapy, citing Category 1 data for high‐grade Ta, all T1, and any Tis tumours.
Maintenance BCG therapy may be the most important advance in BCG treatment of bladder cancer since the initial introduction. The risk of tumour recurrence and disease progression is life‐long in most patients, but the immune stimulation induced by BCG wanes with time.
Logarithmic dose reduction of BCG in patients with increasing side‐effects will typically prevent escalation of toxicity.
Simple dose reduction, appropriate antibiotics, and understanding treatment contraindications have greatly increased the safety of BCG. The 3‐week maintenance schedule for 3 years has been evaluated in randomised clinical trials and appears to be the current optimal treatment.
With the success achieved in bladder cancer and the relative safety and economy of BCG, consideration should be given to further research for its effectiveness in other genitourinary malignancies.
Rescue intravesical therapies for patients with bacillus Calmette-Guérin failure nonmuscle invasive bladder cancer remain a critical focus of ongoing research. Sequential intravesical gemcitabine and ...docetaxel therapy has shown safety and efficacy in 2 retrospective, single institution cohorts. This doublet has since been adopted as an intravesical salvage option at multiple institutions. We report the results of a multi-institutional evaluation of gemcitabine and docetaxel.
Each institution retrospectively reviewed all records of patients treated with intravesical gemcitabine and docetaxel for nonmuscle invasive bladder cancer between June 2009 and May 2018. Only patients with recurrent nonmuscle invasive bladder cancer and a history of bacillus Calmette-Guérin treatment were included in the analysis. If patients were disease-free after induction, maintenance was instituted at the treating physician's discretion. Posttreatment surveillance followed American Urological Association guidelines. Survival analysis was performed using the Kaplan-Meier method and risk factors for treatment failure were assessed with Cox regression models.
Overall 276 patients (median age 73 years, median followup 22.9 months) received treatment. Nine patients were unable to tolerate a full induction course. One and 2-year recurrence-free survival rates were 60% and 46%, and high grade recurrence-free survival rates were 65% and 52%, respectively. Ten patients (3.6%) had disease progression on transurethral resection. Forty-three patients (15.6%) went on to cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasion. Analysis identified no patient, disease or prior treatment related factors associated with gemcitabine and docetaxel failure.
Intravesical gemcitabine and docetaxel therapy is well tolerated and effective, providing a durable response in patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin therapy. Further prospective study is warranted.
Purpose We assessed the safety, pharmacokinetics and anticancer activity of intravesical CG0070, a cancer selective, replication competent adenovirus, for the treatment of nonmuscle invasive bladder ...cancer. Materials and Methods A total of 35 patients received single or multiple (every 28 days × 3 or weekly × 6) intravesical infusions of CG0070 at 1 of 4 dose levels (1 × 1012 , 3 × 1012 , 1 × 1013 or 3 × 1013 viral particles). Response to treatment was based on cystoscopic assessment and biopsy or urine cytology. Urine and plasma CG0070, and granulocyte-monocyte colony-stimulating factor were measured in all patients. A subset of 18 patients was assessed for retinoblastoma phosphorylation status. Results Grade 1–2 bladder toxicities were the most common adverse events observed. A maximum tolerated dose was not reached. High levels of granulocyte-monocyte colony-stimulating factor were detected in urine after administration in all patients. Virus replication was suggested based on an increase in urine CG0070 genomes between days 2 and 5 in 58.3% of tested patients (7 of 12). The complete response rate and median duration of the complete response across cohorts was 48.6% and 10.4 months, respectively. In the multidose cohorts the complete response rate for the combined groups (every 28 days and weekly × 6) was 63.6% (14 of 22 patients). In an exploratory, retrospective assessment patients with borderline or high retinoblastoma phosphorylation who received the multidose schedules had an 81.8% complete response rate (9 of 11). Conclusions Intravesical CG0070 was associated with a tolerable safety profile and antibladder cancer activity. Granulocyte-monocyte colony-stimulating factor transgene expression and CG0070 replication were also suggested.
CG0070 is a replication-competent oncolytic adenovirus that targets bladder tumor cells through their defective retinoblastoma pathway. Prior reports of intravesical CG0070 have shown promising ...activity in patients with high-grade non–muscle invasive bladder cancer (NMIBC) who previously did not respond to bacillus Calmette-Guérin (BCG). However, limited accrual has hindered analysis of efficacy, particularly for pathologic subsets. We evaluated interim results of a phase II trial for intravesical CG0070 in patients with BCG-unresponsive NMIBC who refused cystectomy.
At interim analysis (April 2017), 45 patients with residual high-grade Ta, T1, or carcinoma-in-situ (CIS) ± Ta/T1 had evaluable 6-month follow-up in this phase II single-arm multicenter trial (NCT02365818). All patients received at least 2 prior courses of intravesical therapy for CIS, with at least 1 being a course of BCG. Patients had either failed BCG induction therapy within 6 months or had been successfully treated with BCG with subsequent recurrence. Complete response (CR) at 6 months was defined as absence of disease on cytology, cystoscopy, and random biopsies.
Of 45 patients, there were 24 pure CIS, 8 CIS + Ta, 4 CIS + T1, 6 Ta, 3 T1. Overall 6-month CR (95% CI) was 47% (32%–62%). Considering 6-month CR for pathologic subsets, pure CIS was 58% (37%–78%), CIS ± Ta/T1 50% (33%–67%), and pure Ta/T1 33% (8%–70%). At 6 months, the single patient that progressed to muscle-invasive disease had Ta and T1 tumors at baseline. No patients with pure T1 had 6-month CR. Treatment–related adverse events (AEs) at 6 months were most commonly urinary bladder spasms (36%), hematuria (28%), dysuria (25%), and urgency (22%). Immunologic treatment–related AEs included flu-like symptoms (12%) and fatigue (6%). Grade III treatment–related AEs included dysuria (3%) and hypotension (1.5%). There were no Grade IV/V treatment–related AEs.
This phase II study demonstrates that intravesical CG0070 yielded an overall 47% CR rate at 6 months for all patients and 50% for patients with CIS, with an acceptable level of toxicity for patients with high-risk BCG-unresponsive NMIBC. There is a particularly strong response and limited progression in patients with pure CIS.
•Overall 6-month complete response rate of 47% in patients with high-risk BCG-unresponsive NMIBC.•A 58% 6-month complete response in patients with pure CIS; 50% 6-month complete response for patients with CIS-containing tumors.•Overall toxicity was acceptably low.
Objective
To provide a contemporary update and recommendations for the diagnosis and management of low‐grade non‐muscle‐invasive bladder cancer (BCa) based on current literature and expert consensus ...of the International Bladder Cancer Group.
Methods
We reviewed published trials, guidelines, meta‐analyses and reviews (up to March 2019) and provide recommendations on baseline evaluations, treatment, endpoints, study design and surveillance protocols.
Results
Low‐grade Ta BCa poses minimal risk to patients in terms of progression and disease‐specific survival. Thus, to minimize patient morbidity, this entity should be managed appropriately. After initial diagnosis of low‐grade Ta tumour, subsequent stable, low‐grade‐appearing recurrences can be managed conservatively with office cystoscopy and fulguration or even followed using an active surveillance protocol. Intravesical therapy other than single‐dose peri‐operative chemotherapy instillation should be used judiciously, and only after assigning appropriate risk points. Routine use of urinary cytology – other than at initial risk stratification, or for patients on active surveillance without therapy – is not recommended; and surveillance cystoscopy may be discontinued after 5 years. Clinical studies in this group of patients should focus on recurrence rates, and time to recurrence, rather than progression events.
Conclusions
The International Bladder Cancer Group has developed formal recommendations regarding the diagnosis, treatment and surveillance of low‐grade non‐muscle‐invasive BCa to minimize morbidity and encourage uniformity among studies in this disease.
In the United States, bladder cancer is the fourth most common human malignancy. In the past decade, the incidence of bladder cancer has increased by 36%. However, mortality has declined by 8%. ...Intravesical chemotherapy was considered to be partially responsible for this improvement in survival, but a recent review of clinical studies shows no reduction in disease progression with intravesical chemotherapy. Fortunately, the results of immunotherapy with bacille Calmette-Guérin (BCG) are quite different, and it is expected that patients treated with optimal BCG treatment regimens will have a long-term reduction in tumor recurrence, tumor progression, and cancer mortality.
PURPOSEWe investigated the safety, preliminary efficacy, and immune effects of large surface area microparticle docetaxel (LSAM-DTX) administered by direct injection after transurethral resection of ...bladder tumor (TURBT), and by intravesical instillation in high-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODSThe trial followed an open-label 3+3 dose escalation with additional enrollment at the high dose. After TURBT, subjects received direct injection LSAM-DTX into the resection site and intravesical LSAM-DTX, followed by 6-week induction and 3-week maintenance intravesical LSAM-DTX courses. Tumor recurrence was evaluated by cytology, cystoscopy, or biopsy. Pharmacokinetic analysis of blood and multiplex immunofluorescence of tumor microenvironment occurred pre- and post-LSAM-DTX. RESULTSNineteen subjects were enrolled, 14 with prior bacillus Calmette-Guérin exposure and 16 with ≥1 prior TURBT. Direct injection and intravesical LSAM-DTX were well tolerated. In the 3 lowest dose escalation cohorts the median recurrence-free survival was 5.4 months (10 patients, median followup 8.6 months). In the high-dose and expansion cohorts median recurrence-free survival was significantly increased (p <0.05, hazard ratio 0.29) to 12.2 months (9 patients, median followup 12.4 months). Systemic docetaxel exposure was negligible and increases in antitumor immune cells were found in the tumor microenvironment along with elevations in the PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitor targets. CONCLUSIONSPost-TURBT direct injection and intravesical LSAM-DTX were well tolerated and demonstrated clinical response for patients with high-risk nonmuscle-invasive bladder cancer. Favorable immune cell infiltration and checkpoint receptor increases following LSAM-DTX treatment warrants investigation alone as well as in combination with immune checkpoint inhibitor therapy.
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