Cost‐effectiveness analysis of immediate radical cystectomy versus intravesical Bacillus Calmette‐Guerin therapy for high‐risk,high‐grade (T1G3) bladder cancer

BACKGROUND:

Although both radical cystectomy and intravesical immunotherapy are initial treatment options for high‐risk, T1, grade 3 (T1G3) bladder cancer, controversy regarding the optimal strategy persists. Because bladder cancer is the most expensive malignancy to treat per patient, decisions regarding the optimal treatment strategy should consider costs.

METHODS:

A Markov Monte‐Carlo cost‐effectiveness model was created to simulate the outcomes of a cohort of patients with incident, high‐risk, T1G3 bladder cancer. Treatment options included immediate cystectomy and conservative therapy with intravesical Bacillus Calmette‐Guerin (BCG). The base case was a man aged 60 years. Parameter uncertainty was assessed with probabilistic sensitivity analyses. Scenario analyses were used to explore the 2 strategies among patients stratified by age and comorbidity.

RESULTS:

The quality‐adjusted survival with immediate cystectomy and BCG therapy was 9.46 quality‐adjusted life years (QALYs) and 9.39 QALYs, respectively. The corresponding mean per‐patient discounted lifetime costs (in 2005 Canadian dollars) were $37,600 and $42,400, respectively. At a willingness‐to‐pay threshold of $50,000 per QALY, the probability that immediate cystectomy was cost‐effective was 67%. Immediate cystectomy was the dominant (more effective and less expensive) therapy for patients aged <60 years, whereas BCG therapy was dominant for patients aged >75 years. With increasing comorbidity, BCG therapy was dominant at lower age thresholds.

CONCLUSIONS:

Compared with BCG therapy, immediate radical cystectomy for average patients with high‐risk, T1G3 bladder cancer yielded better health outcomes and lower costs. Tailoring therapy based on patient age and comorbidity may increase survival while yielding significant cost‐savings for the healthcare system. Cancer 2009. © 2009 American Cancer Society.     

Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder

BACKGROUND: Perioperative cisplatin-based chemotherapy has shown benefit in patients with high-risk localized urothelial bladder cancer, but it is not widely used. Renal impairment may be a major factor limiting its use. The current study was designed to determine the proportion of patients ineligible to receive adjuvant cisplatin-based chemotherapy based on inadequate renal function alone. METHODS: Patients who underwent radical cystectomy for urothelial cancer of the bladder with evidence of extravesical disease (> or =pT3 or any N+) were identified. Patients who received neoadjuvant chemotherapy were excluded. Serum creatinine immediately before and nadir serum creatinine after cystectomy were used to calculate creatinine clearance (CrCl) or glomerular filtration rate (GFR) using the Cockroft-Gault (CG), Jelliffe, and Modification of Diet in Renal Disease (MDRD) study formulas. A cutoff of CrCl <60 mL/min or GFR <60 mL/min/1.73 m2 was used to determine ineligibility for cisplatin-based chemotherapy. The proportion of patients ineligible by each formula was compared by univariate logistic regression. Univariate linear regression was performed to determine the effect of age on CrCl or GFR. RESULTS.: Most patients were pT3 or greater; 39% were lymph node-positive. The overall proportion of patients ineligible for cisplatin-based chemotherapy was 28% by the CG formula, 52% by Jelliffe, and 24% by MDRD. Concordance between formulas was low. With all formulas the probability of ineligibility increased with age: by the CG equation, >40% of patients age >70 years were ineligible. CONCLUSIONS.: The widespread use of cisplatin-based perioperative chemotherapy in patients with high-risk localized bladder cancer may be significantly limited by the high prevalence of baseline renal insufficiency in this population. This finding is most striking in the elderly. Better selection of patients who may safely receive cisplatin and more effective regimens devoid of cisplatin are required to optimize outcomes in this group of patients.     

Superficial bladder cancer

Opinion statement Superficial bladder cancer can be resected with minimal morbidity, but the patients are at high risk for tumor recurrence. Tumors can be divided into low-, intermediate-, and high-risk categories based on tumor grade, stage, and pattern of recurrence. Low-risk tumors are best treated with a single instillation of chemotherapy such as thiotepa, doxorubicin, or mitomycin. Intermediate-risk tumors can be treated with chemotherapy, but, similar to high-risk tumors, will often require immunotherapy. High-risk tumors are best treated with intravesical bacille Calmette-Guerin (BCG) using a 3-week maintenance schedule. Side effects of BCG immunotherapy can be reduced by logarithmic reductions in the dosage of BCG. Patients who fail BCG may be rescued with BCG plus interferon-alfa or radical cystectomy.     

Reactive antibodies against bacillus Calmette‐Guerin heat‐shock protein‐65 potentially predict the outcome of immunotherapy for high‐grade transitional cell carcinoma of the bladder

BACKGROUND:

Intravesical immunotherapy with Mycobacterium bovis (M. bovis) bacillus Calmette‐Guerin (BCG) is the current standard of care against superficial, high‐grade transitional cell carcinoma (TCC) of the urinary bladder (carcinoma in situ and pathologic T1, grade 3 disease). However, individual patient outcome is barely predictable because of the lack of serum markers. Consequently, progression to muscle‐invasive bladder cancer and critical delay of treatments (such as neoadjuvant combination chemotherapy and/or radical cystectomy) often occur. The objectives of this study were to identify a marker for measuring the BCG‐induced immune response and to predict the outcomes and potential improvements of BCG immunotherapy.

METHODS:

Because host immunoresponse mediates BCG activity, the authors screened a combinatorial random peptide library on the circulating pool of immunoglobulins (Igs) purified from an index patient after successful BCG immunotherapy to identify the corresponding target antigen(s).

RESULTS:

An immunogenic peptide motif was selected, isolated, and validated from M. bovis BCG heat‐shock protein 65 (HSP‐65) as a dominant epitope of the humoral response to treatment. Increasing IgA and IgG anti‐HSP‐65 titers specifically predicted a positive patient outcome in a cohort of patients with bladder cancer relative to several cohorts of control patients.

CONCLUSIONS:

The current results indicated that antibody production against M. bovis BCG HSP‐65 can serve as a serologic marker for the predictive outcome of BCG immunotherapy. Subsequent studies will determine the value of this candidate marker to modify BCG‐based treatment for individual patients with bladder cancer. Cancer 2010. © 2009 American Cancer Society.     

Localized bladder cancer

Opinion statement Transitional cell carcinoma (TCC) of the bladder makes up 90% of bladder cancers. The approach to the management of localized TCC includes accurate clinical and histologic diagnosis and staging with pathologic material obtained through endoscopy. Once the diagnosis of superficial TCC has been established, histologically based prognostic factors guide which therapy or combination of therapies is indicated in the management of individual patients. Surgery alone (transurethral resection) is appropriate initial therapy for noninvasive papillary TCC. For lamina propria invasive tumors and carcinoma in situ, intravesical immunotherapy with bacille Calmette-Guérin (BCG) is often the first line of treatment to decrease tumor recurrence and to possibly decrease progression and improve survival. Intravesical chemotherapy and interferon are alternative therapies that can also decrease recurrence rates. For BCG-refractory TCC, durable response rates with alternative intravesical therapies are low. For superficial TCC that is refractory to endoscopic procedures and intravesical agents or for disease progression, radical cystectomy with neobladder formation or other forms of urinary diversion is the treatment of choice.     

尿路上皮癌免疫治疗的研究进展

尿路上皮癌（UC）是泌尿系统常见的恶性肿瘤之一,其发病率及死亡率较高,几十年来,标准的治疗方案仍是基于顺铂的化学疗法,但是不良反应较大且疗效不佳。目前越来越多的免疫检查点抑制剂在治疗UC中显示出良好的疗效和安全性,在精密医学时代,UC的未来在于使用疗效更确切、不良反应更小、更有针对性的治疗。同样,开发可靠的预测生物标志物以及创新的治疗组合方法势在必行。本文将对近年来尿路上皮癌免疫治疗的研究进展及未来展望进行综述。     

Efficacy of combined intravesical immunotherapy and chemotherapy for non-muscle invasive bladder cancer

Intravesical immunotherapy using attenuated bacillus Calmette-Guérin (BCG) strains and intravesical chemotherapy are the modalities most commonly used to treat intermediate- or high-risk patients with non-muscle invasive bladder cancer. BCG has been shown to decrease recurrence rates by up to 67% compared with tumor resection alone, but intensive BCG maintenance regimens are poorly tolerated in a large proportion of patients. Intravesical chemotherapy also decreases the risk of recurrence for these patients, but has diminished efficacy compared with BCG. If BCG dose reduction can be achieved with combined intravesical immunotherapy and chemotherapy, this regimen may improve compliance and thus optimize treatment for these patients by limiting side effects from BCG monotherapy, while at the same time improving oncologic efficacy via the separate anti-tumor mechanisms of these agents. The authors discuss the most recent data regarding combining these agents in an alternating or sequential regimen.     

Is BCG an “Orphan” Drug Suffering from Chemotherapists' Overkill?

Modern interest in cancer immunotherapy emerged in 1969 following the pioneer reports of George Mathe on the effect of Bacillus Calmette-Guerin (BCG) in suppressing murine cancer and apparently increasing survival of children with acute lymphatic leukemia (1). Mathe employed intensive repeated weekly multisite scarifications with BCG during both the induction and maintenance phases of the steadily improving chemotherapy in vogue in the late 1960s. His favorable but uncontrolled studies stimulated a number of “historically controlled” trials of intensive heavy weekly BCG treatment. In the last eight years, at least 60 randomized controlled trials and many other nonrandomized studies have been completed. These employ diverse immunomodulators including various formulations of BCG (2) and BCG derivatives [BCG-MER, BCG cell wall skeletons (CWS)], as well as Corynebacterium parvumlevamisole, thymosin, poly A-poly U, and other agents. A vast array of confusing fragmentary observations and generally nonsignificant borderline findings have been summarized in several published international symposia.     

基于免疫检查点PD-1的肿瘤免疫耐药机制及耐药后再治疗的策略

免疫治疗被认为是继手术、放疗和化疗后的第四种肿瘤治疗方法。近年来随着对免疫治疗特别是免疫检查点抑制剂研究的深入,PD-1/PD-L1通路抑制剂被批准用于许多癌种的治疗,但由于肿瘤细胞通过多种耐药机制规避免疫应答,免疫检查点阻断存在整体应答率低、原发或继发性耐药等难题。本文阐述了肿瘤免疫耐药的机制,探讨了耐药后再治疗的策略,为提高免疫检查点抑制剂的应答率、降低免疫耐药发生的概率提供理论和临床依据。     

Erstlinienchemotherapie beim Harnblasenkarzinom

The incidence of bladder cancer in Europe was estimated to be 133,700 cases in 2008 (104,600 males and 29,100 females) corresponding to 6.2?% of tumors in men and 1.9?% in women. The incidence of these tumors has therefore not substantially changed in 5 years (WHO Globocan project 2008). Cisplatin-containing combination chemotherapy has been the standard of care in the treatment of urothelial cancer (UC) since the late 1980s. Gemcitabine/cisplatin, MVAC, high-dose MVAC and the new triplet paclitaxel/cisplatin/gemcitabine are possible treatment options with different toxicity profiles. However, up to 50% of patients are unfit for cisplatin-containing chemotherapy, either due to a poor performance status (PS) and/or impaired renal function or due to co-morbidities that prevent high-volume hydration. These conditions increase with age. There is controversy about the definition of fit or unfit for cisplatin therapy. An international survey revealed five factors to be crucial: decreased PS, renal function impairment, peripheral neuropathy, hearing loss and heart failure. A standard chemotherapy has not yet been established for patients ineligible for cisplatin-based standard chemotherapy. Trials with clearly defined unfit patients or patients with multiple adverse prognostic factors are rare. The first randomized phase II/III trial in this setting compared carboplatin/vinblastin/methotrexate (M-CAVI) and carboplatin/gemcitabine (CG) in patients unfit for cisplatin. Overall survival (OS) was not statistically significantly different between the two treatment regimens with a median OS of 9.3 and 8.1 months for CG and M-CAVI, respectively. Severe acute toxicity was higher for the M-CAVI arm and therefore carboplatin/gemcitabine is the preferred treatment option in cisplatin ineligible patients.     

Neoadjuvant Paradigm for Accelerated Drug Development: An Ideal Model in Bladder Cancer

Neoadjuvant cisplatin‐based combination chemotherapy for muscle‐invasive bladder cancer (MIBC) has been shown to confer a survival advantage in two randomized clinical trials and a meta‐analysis. Despite level 1 evidence supporting its benefit, utilization remains dismal with nearly one‐half of patients ineligible for cisplatin‐based therapy because of renal dysfunction, impaired performance status, and/or coexisting medical problems. This situation highlights the need for the development of novel therapies for the management of MIBC, a disease with a lethal phenotype. The neoadjuvant paradigm in bladder cancer offers many advantages for accelerated drug development. First, there is a greater likelihood of successful therapy at an earlier disease state that may be characterized by less genomic instability compared with the metastatic setting, with an early readout of activity with results determined in months rather than years. Second, pre‐ and post‐treatment tumor tissue collection in patients with MIBC is performed as the standard of care without the need for research‐directed biopsies, allowing for the ability to perform important correlative studies and to monitor tumor response to therapy in “real time.” Third, pathological complete response (pT0) predicts for improved outcome in patients with MIBC. Fourth, there is a strong biological rationale with rapidly accumulating evidence for actionable targets in bladder cancer. This review focuses on the neoadjuvant paradigm for accelerated drug development using bladder cancer as the ideal model.     

Tackling non-muscle invasive bladder cancer in the clinic

Introduction: Non-muscle invasive bladder cancer (NMIBC) is a common disease process with a high propensity for recurrence and risk of progression to muscle-invasive or systemic disease. Optimal management of NMIBC depends on appropriate resection and staging, risk-based use of intravesical therapy and tailored surveillance. Current challenges include compliance with guideline recommendations and cancers which are refractory to standard therapies.

Areas covered: This review summarizes the conventional management of NMIBC – which relies on strict cystoscopic surveillance and intravesical therapies with chemotherapy and/or immunotherapy in the form of bacillus Calmette-Guerin (BCG). As many patients will be resistant to conventional treatment, investigational therapies and novel prognostic models will also be discussed.

Expert commentary: For decades, the management of NMIBC has been predicated on intravesical therapies, most often through the instillation of BCG which has proven clinical efficacy over transurethral resection alone. Despite this, many patients will recur or progress after BCG therapy. While radical cystectomy remains the standard for such patients, suitable alternatives are being actively investigated. An increased interest in immunotherapy for malignancy has reinvigorated this field and on-going advances in disease prognostication are likely to improve upon the existing treatment paradigms for NMIBC.     

Effect of preoperative intralesional BCG and postoperative 5-FU chemotherapy in three adenocarcinoma lines in rats.

In No. 13762 mammary adenocarcinoma, it has been shown that the combination of tumor infiltration with BCG and of subsequent surgery is more curative than either treatment modality alone. And the administration of postoperative systemic 5-fluorouracil (D-FU) is equally effective in eliminating the visceral metastasis and prolonging the host survival. In the experiments reported here, two other spontaneously metastasizing adenocarcinoma lines were similarly treated. Postoperative 5-FU chemotherapy, but not intralesional BCG, significantly improved survival duration of rats with SMT-2A mammary adenocarcinoma, but neither chemotherapy nor BCG immunotherapy was effective in the new colonic adenocarcinoma line.     

First line chemotherapy for advanced ovarian cancer in 2000: standards and questions

Ovarian cancer is wellknown to be chemosensitive since more than thirty years. However, long term results of this disease remain low. That's why standard first line chemotherapy is evolving to attempt to increase disease free survival and overall survival. Before cisplatin, standard chemotherapy was an alkylant used alone, mainly melphalan. With cisplatin disponibility, cisplatin based chemotherapy like cisplatin-cyclophosphamide with or without doxorubicin (CP or CAP) is used. Carboplatin can replace cisplatin because theses two platinum compounds have the same tumoral efficacy. Carboplatin is less toxic and its administration is more easy; so carboplatin with cyclophosphamide is actually the standard combination for elderly patients. Paclitaxel-cisplatin or carboplatin became the new actual standard combination. However, questions are asked concerning first-line chemotherapy for advanced ovarian cancer. Some of them are resolved like optimal number of cycles (6 in average), intensity-dose of cisplatin (25 mg/m2/week or 75 mg/m2 every 3 weeks) or for carboplatin (300 mg/m2 every 3 weeks or dose calculation according to AUC of 5 to 7.5 mg/ml x min). Another questions are ongoing like the place of anthracyclins or new drugs in front-line, the use of intra-peritoneal way for cisplatin and the role of intensive chemotherapy or immunotherapy as consolidation.     

A systematic overview of chemotherapy effects in urothelial bladder cancer.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for urothelial bladder cancer is based on 234 scientific reports including two meta-analyses, 75 randomised studies and 143 other prospective studies, and totally comprising 31,974 patients. The conclusions reached can be summarised into the following points: Intravesical chemotherapy administered in an adjuvant setting to transurethral resection (TUR-B) of superficial tumour reduces short-term (one to three years) recurrence rate by approximately 20%. After a median follow-up of eight years, 8%, fewer recurrences were seen after intravesical chemotherapy. Long-term maintenance instillation chemotherapy ( > 1 year) does not further increase the recurrence-free interval nor the long-term recurrence rate when compared with immediate postoperative short-term intravesical chemotherapy. The majority of studies on intravesical Bacillus Calmette-Guerin (BCG) vs intravesical chemotherapy show superior protection from tumour recurrence for BCG. Despite prolongation of the disease-free survival, adjuvant intravesical chemotherapy has, in the majority of studies, no apparent long-term impact on the evolution of superficial into muscle invasive bladder cancer. There are no data showing a survival benefit from adjuvant intravesical chemotherapy. Chemotherapy with cisplatin-based regimens induce objective tumour response in at least 50% of patients with metastatic disease. A prolonged disease-free and overall survival (median two to three months) is seen in patients treated with cisplatin-based polychemotherapy compared with patients treated with cisplatin alone or less intensive chemotherapy. With the exception of one randomised study, there are no conclusive data on possible survival benefit for patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy prior to cystectomy or radiotherapy. Although the results from use of adjuvant chemotherapy after surgery or curative radiotherapy obtained are promising, the small studies performed lack statistical power and, hence, there is insufficient data to make any conclusion regarding a possible survival benefit from adjuvant chemotherapy. A growing body of data indicate that bladder preservation can be achieved by multi-modality approach in selected patients and that survival in these is similar to that seen after radical cystectomy, but randomised trials are still lacking.     

Bacillus Calmette-Guerin (BCG) in the treatment of superficial bladder cancer

Intravesical therapy is currently being used in the management of superficial transitional cell carcinoma of the urinary bladder. Its main objectives constitute treatment of existing or residual tumor, prevention of recurrence of tumor, prevention of disease progression, and prolongation of survival. The initial clinical stage and grade of bladder cancer remains the main determinant factors in survival, irrespective of the treatment. Intravesical chemotherapy has shown a decrease in short-term tumor recurrence rates, but has had no positive impact on disease progression or prolongation of survival. Bacillus Calmette-Guerin (BCG) immunotherapy remains the most effective treatment and prophylaxis modality for superficial bladder cancer and results in a positive outcome on tumor recurrence, disease progression, and prolongation of survival. Although therapy by intravesical BCG instillation is widely accepted as the therapy of choice, the development of BCG-resistant bladder cancer remains a major setback. Thus, there is an urgent need for a major effective therapy for bladder cancer patients who are unresponsive to BCG therapy. This review summarizes briefly the recent highlights and advances in the therapy of superficial bladder cancer. This review also describes our preliminary findings achieved in in vitro model systems and our proposed new approaches to overcome the resistance of bladder cancer cells and render bladder cancer cells responsive to these new therapies.     

Pembrolizumab for the treatment of bladder cancer

Introduction: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies.

Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab.

Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy.     

Interspersion of cyclophosphamide and BCG in the treatment of L1210 leukemia and Lewis Tumor

The therapeutic value of interspersing cyclophosphamide (CPM) chemotherapy and BCG immunotherapy was investigated in two tumor models: L1210 leukemia and Lewis solid tumor (LLT). In the case of L1210 leukemia, the antileukemic effect of CPM was enhanced by subsequent BCG administration where a single cycle of combined treatment was applied; treatment by repeated doses of CPM interspersed with BCG was no more effective than CPM chemotherapy alone. In the case of LLT tumor, the effect of one cycle of combined CPM-BCG treatment was not different from CPM administered alone but treatment by repeated doses of CPM interspersed with BCG immunotherapy was less effective than CPM chemotherapy alone. These results indicate that, while the effect of BCG immunotherapy may be favorable or nil when BCG is applied after cell-reducing chemotherapy, it may be nil or unfavorable when applied repeatedly in interspersed chemoimmunotherapy treatments.     

非小细胞肺癌免疫治疗研究进展

近年来,肺癌的治疗手段层出不穷,从传统化疗到靶向药物,再到免疫检查点抑制剂的出现,很大程度上改善了患者的预后,延长了患者生存期。免疫检查点抑制剂的应用,即免疫治疗,一改传统的治疗方式,作用于程序性细胞死亡蛋白-1（PD-1）及其配体（PD-L1）发挥有效且持久的抗肿瘤反应。本文主要介绍了近年来免疫治疗一线、二线应用于非小细胞肺癌（NSCLC）的研究情况,影响免疫治疗疗效的因素,及免疫治疗的相关毒副反应。