Urologia Journal

Risk factors analysis in bladder cancer should consider not only the clinical and pathological features of the tumor but also environmental and lifestyle factors. They may play, in fact, a relevant role not only in the pathogenesis but also in the biological behavior of the tumor. The association between cigarette smoking and bladder cancer has been consistently confirmed in several case-control and cohort studies. The risk of bladder cancer seems to increase with duration and intensity of smoking. Another environmental risk factor, although not definitively proved, is water supply. Chlorination or water pollution by pesticides and other chemical factors is considered a relevant risk factor. Familiarity and genetic predisposition, diet and individual risk factors should be taken into account.

Bladder cancer has the highest lifetime treatment and surveillance costs per patients for all cancers. New diagnostic tools, and ancillary tests, such as urine markers, have been developed to enhance the sensitivity for detecting cancer cells exfoliated from the urinary tract, and to reduce the discomfort of repeated cystoscopies. Several markers have been studied, and others are under investigation; a few provide some advantage, only in selected cases, in terms of detection rate and cost-effectiveness for the patient as well as the health service. This paper provides a concise update of the most promising urinary markers (nuclear matrix protein 22, ImmunoCyt, and fluorescence in situ hybridization) acting as non-invasive tests which help to identify urothelial cancers. Cystoscopy remains the most consistent examination for diagnosis and follow-up of non-muscle-invasive bladder cancer. However, some markers can be useful in understanding atypical cytology due to urinary tract phlogosis, infection, or treatment with chemotherapy or intravesical bacillus Calmette-Guérin. Moreover, in centers with clinical experience, selected patients may benefit from the use of urinary markers to achieve prognostic information at the specific time of individual follow-up.

Cystoscopy is a common procedure in the urological practice due to its ability to survey the bladder for a variety of indications. It is the principal means of diagnosis and surveillance of bladder tumors. Hematuria is the most common finding of non-muscle-invasive bladder cancer (NMIBC), as a consequence of that it is one of the most frequent reasons to perform cystoscopy.

The follow-up of patients treated for NMIBC is of great importance because of the high incidence of recurrence and progression of the disease, whereby patients with NMIBC undergo cystoscopy repeatedly (every three months generally). At present, the schedule and methods of follow-up is a sign of patient's progression and recurrence risk, which has to be rated for each patient when follow-up begins.

Moreover, before the development of flexible cystoscopy, patients underwent rigid cystoscopy with greater discomfort. The advance of flexible cystoscopy has significantly decreased the pain and discomfort associated with the procedure, and the flexible instrument is currently considered the standard tool to perform cystoscopy. However, controversies exist about the use of anesthetic gel during cystoscopy.

The aim of this study is to report some short evidence about cystoscopy in particularly about the follow-up timing for NMIBC and the use of rigid or flexible cystoscopy.

Trans-Urethral Resection (TUR) of bladder tumors is the gold standard to make the correct diagnosis and remove all visible lesions. The strategy of resection depends on the size of the lesion. Small tumors can be resected en bloc, while larger tumors should be resected separately in fractions to obtain a correct pathological diagnosis. Random biopsies from normal-looking mucosa should be performed in patients with positive urinary cytology and absence of visible tumor in the bladder. As a standard procedure, cystoscopy and TUR are performed using white light. Photodynamic diagnosis (PDD) is most useful for detecting CIS, and therefore should be restricted to those patients with a suspected high-grade tumor.

Bladder cancer care continues to represent a significant financial burden on the population and on the healthcare system. The incidence of bladder cancer has increased over the last two decades. Therapeutic advances have occurred in bladder cancer care, but at an increased cost to payers, providers, and patients. Intravesical treatment of non-muscle invasive tumors represents one of the main costs. For this reason therapeutic schedules need to be rationalized. In this perspective, we present some critical remarks on: the use of gemcitabine in clinical practice; the real impact of the perioperative chemotherapy, emphasizing the cost and effectiveness in high-risk patients, and finally the optimization of intravesical treatments.

There is a need for the scientific community to focus on their resources and convey efforts not in the treatment of low-risk cancers (present in significant numbers in various studies), which the Anglo-Saxons call “nuisance tumor” since they can be treated easily and effectively at low cost, but definitely to engage in the study of the treatment of cancer at high risk of recurrence and progression, and it is on this field that the cost (economic, management, subjective) / benefit ratio must be assessed.

A shortage of BCG is foreseen till the end of 2013.

Which will be the management of intermediate and high-risk NMI-BC if BCG will not be available? In patients harboring high-risk NMI tumors, particularly T1G3 and Tis, the first therapeutic choice is radical cystectomy. Device-assisted therapies, although showing promising results, should be considered only for selected patients.

In intermediate risk patients, intravesical chemotherapy remains a legitimate option even if BCG is available. Thus, in a period of BCG shortage, intravesical chemotherapy should be offered, preferably preceded by early instillation, according to the EAU guidelines.

Intravesical therapy is widely used in non-muscle-invasive bladder cancer (NMIBC) as adjuvant treatment after transurethral resection of bladder tumor (TURBT). Assuming that adjuvant therapy is necessary for NMIBC in order to reduce recurrence and progression rates, chemotherapy and BCG toxicity become a relevant issue. Both treatments may have local and systemic side effects, which can lead to treatment cessation, resulting in incomplete treatment and poor outcomes. Therefore, urologists, specialist nurses and patients must be aware of the possible adverse events in order to early recognize, prevent and treat them properly. This article summarizes the local and systemic side effects associated with intravesical therapy, presents the recommendations for an effective management of these adverse events based on currently available evidence, and highlights some open questions on these issues.

Among the objectives outlined in the National Health Plan 1998-2000 are some interventions to improve the safety of public and private health-care facilities.

One of the significant risks in the health sector is the one resulting from exposure to chemotherapy drugs.

The Health Surveillance must take into account that anticancer drugs are cytotoxic compounds, which can cause cancer.

It is necessary that occupational exposure to antineoplastic agents be kept within the lowest possible level.

The potential absorption due to exposure to chemotherapy may be significantly reduced by adopting preventive measures specific to particular concern in a centralization of structures and activities.

To ensure an adequate system of protection for people who use these substances in professional health-care settings, there should be the establishment of a specific “Anticancer Drugs Unit” to entrust the working cycle.

The places reserved for the preparation of cytotoxic chemotherapy must be equipped with floor and walls up to heights of appropriate plastic material easily washable.

Inside the room there must be a “point of decontamination” for washing hands and eyes.

The preparation of antineoplastic agents should be performed under hoods positioned away from heat sources and any air currents.

It is advisable to use disposable surgical gowns with long sleeves with elastic cuffs or knitted sleeve to allow the gloves sticking above the gown itself.

In the preparation of drugs the vial opening procedure must be implemented after verifying that no liquid is left at the top, and by wrapping the neck of the vial with a sterile gauze.

Any accidental contamination must be reported to the Physician.

All waste materials produced from the handling of cytotoxic chemotherapy should be considered as special hospital waste.

To achieve high standards of safety and prevention for the personnel exposed to antineoplastic agents, it is necessary that workers are adequately informed about the risks and proper handling and disposal of anticancer drugs and contaminated materials.

Non-muscle-invasive bladder cancer is a common urinary malignancy whose management is a challenge: strong evidence supports the use of passive intravesical chemotherapy in the management of this tumor. Despite current guidelines, the treatment is suboptimal as illustrated by the high risk of recurrence and progression. Bacillus Calmette-Guérin (BCG) is the gold standard for the treatment of high-grade non-muscle-invasive bladder cancer, but in case of disease persistence, after 2 consecutive induction courses of BCG, patients must undergo radical cystectomy.

We discuss options for second-line adjuvant therapy for non-muscle-invasive bladder cancer in standard treatment non-responder patients. We investigated the use and application of device-assisted therapy for the intravesical treatment of bladder cancer, such as thermochemotherapy (TCT) and electromotive drug administration (EMDA). Many studies demonstrate their synergistic therapeutic effect, greater than the single treatment with chemotherapy, inducing an increased absorption of the chemotherapeutic agent (Mitomycin C) to the urothelium. TCT and EMDA are safe and effective in terms of outcomes. For the future it will be important to encourage the use of the existing technology within the appropriate clinical indications.

The term ‘Non-muscle invasive bladder cancer’ identifies a heterogeneous disease due to different natural history of its various appearances. T1 stage represents a non-predictable population, which might respond to non-operative treatment strategies or to the need of a more aggressive treatment, in order to avoid the progression to invasive, and possibly to metastatic stages.

In the first year following transurethral resection of bladder (TURB), tumor recurrence is seen in up to 45% of the population; of this, 15% may progress to muscle invasive or metastatic disease, or both. In order to control the recurrence and progression and identify invasive tumors at the earliest possible stage, it is strongly necessary to define individual patient risk assessment follow-up.

To obtain exact staging, besides a proper transurethral resection of bladder, a restaging transurethral resection of bladder should be performed in T1 patients. Data from literature support the immediate postoperative intravesical instillation of different chemotherapeutic agents in low-risk patients.

Multifocal papillary lesions might require a more intensive adjuvant regimen, whereas intravesical immunotherapy using Bacillus Calmette-Guérin is recommended in patients at high risk of progression. Early cystectomy should be considered in patients with recurrent T1 tumors or refractory carcinoma in situ to avoid unfavorable tumor progression.

Despite the good quality of treatment expected with optimized transurethral resection (TUR) and adjuvant Bacillus Galmette-Guérin (BCG) regimen, many high-risk non-muscle invasive bladder cancer (NMIBC) patients recur and progress. According to the EORTC Tables of risk, cases with a score of 10-17 and those with a score of 7-23 should be considered as being at high risk of recurrence and progression, respectively. AUA and NCCN consider all T1 stage tumors, high grade Ta and CIS at high risk of recurrence and progression. Long-term follow-up shows that T1, G3 patients treated with BCG will suffer from up to 45% and 17% rate of recurrence and progression, respectively. Consequently, EAU, AUA and NCCN Guidelines for bladder cancer recommend radical cystectomy as a first treatment option for those patients who failed after two cycles of adjuvant BCG. However, to date, there is no definitive evidence that in this special subgroup of patients an early radical cystectomy is better than any additional salvage strategy, in terms of oncologic outcome. On the other hand, it is well accepted that radical cystectomy is burdened with consistent reduction of overall post-operative quality of life. The reluctance of patient to accept (and of surgeon to recommend) this major extirpative surgery may explain the reduced disease-free survival rate, well documented when radical cystectomy has been extremely delayed. Defining the criteria for the selection of BCG-failure patients for whom any conservative procedure should be definitively abandoned in favor of a timely radical cystectomy has become of critical importance. Recently, clinical, laboratory and pathologic acquisitions allowed the development of more accurate predictive factors for tumor progression in NMIBC. Among these factors, clinical type of BCG-failure, morphology and tumor growth patterns, pathologic sub-staging and immunohistochemistry will play a paramount role in decision-making with these patients in routine practice.