Bladder Tumors:, 2011 Molecular Aspects and Clinical Management Cancer Drug Discovery and Development Series

Bladder cancer is a common cancer of the urinary tract. It is the fourth leading cause of cancer-related death among men and the seventh among women. Clinical management of bladder cancer is challenging because of the heterogeneity among bladder tumors with respect to invasion and metastasis, frequent occurrence of new tumors in the bladder among patients treated with bladder preservation treatments and poor prognosis of patients with tumors that invade the bladder muscle and beyond. Due to these factors it has been said that the cost per patient of bladder cancer, from diagnosis to death is the highest of all cancers. In addition to it being a significant health problem, bladder cancer is an interesting cancer to study in many ways than one. For example, Environmental factors such as cigarette smoking and other carcinogens play a major role in the development of transitional carcinoma of the bladder, whereas, schitosomasis, a protozoan infection results in squamous cell carcinoma of the bladder. Different molecular pathways with distinct molecular signatures appear to be involved in the development of low-grade versus high-grade bladder tumors. Currently being monitored by an invasive endoscopic procedure, cystectomy, with urine cytology as an adjunct, bladder cancer is at the forefront of developing cancer biomarkers for non-invasive detection. Due to the differences in the invasive and metastatic potential of bladder tumors, treatment options differ depending upon tumor grade and stage. New advances are being made in treatment options to improve the outcome and quality of life for patients with bladder cancer. Similarly, new molecular nomograms are being discovered to predict treatment outcome so that individualized treatment options can be offered to patients.

1. Epidemiology of Bladder Cancer

Bladder cancer is a "carcinogen-driven" cancer. Cigarette smoking, exposure to arylamines have been linked to increased risk for developing bladder cancer. Some other causes, arsenic exposure, hair dressers/hair dyes, etc. Another cause of bladder cancer of a separate type is bilharzial disease/schistosomiasis.

Topics to be covered: Bladder cancer incidence and prevalence world wide, US and Africa (Bilharzial disease).Bladder carcinogens and their correlation to bladder cancer incidence. Field effect theory and is it supported by molecular characterization of recurrent tumors (i.e., is this a recurrence or a new tumor). Bilharzial disease and bladder cancer in Egypt: any molecular link?

Include both EU and USA guidelines.

Possible author: Maria Ribal from Barcelona

2. Molecular Signatures of Bladder Cancer

Bladder tumors have two characteristics: Heterogeneity in invasion and metastasis and frequent recurrence. Studies on molecular determinants of bladder cancer have discovered that low- and high-grade tumors may develop through divergent molecular pathways. However, current molecular signatures do overlap. Part of the reason for this overlap may be some low-grade patients develop high-grade tumors. Topics to be covered: Divergent pathways for the development of low-grade and high-grade tumors. Molecular signatures characteristics of these divergent pathways (FGF-mutations, Ki67, p53 mutations). How definitive are these signatures for predicting the development of low-grade versus high-grade tumors. Development of carcinoma in situ. What are the possible causes of overlap between these divergent pathways. recurrent versus.

Possible authors: Ashraf Bakkar, Dr. Droller.

3. Pathology of Bladder Tumors:
Topics to be covered: TMN classification versus WHO classification; various types of bladder tumors (TCC, adenocarcinoma, squamous carcinoma), tumor grade, and stage.

Possible authors: Arnad Hartmann (Erlangen University) + Isabel Sesterhenn (Washington DC)

4. Bladder cancer diagnosis and detection – Current Status (cystoscopy, upper track imaging): Current mode of bladder cancer detection, AUA guidelines for detecting bladder cancer, cystoscopy, a brief reference to cytology without going into details. Topics to be included: Diagnosis and Staging of bladder cancer; The role of imaging; MRI/CT for local staging of bladder cancer; Imaging of lymph node involvement; Distant metastases

Possible authors: Prof. Richard Sylvester from Brussels or Fred Witjes from Nijmengen Netherlands.

5. Urine Cytology, DNA Ploidy and current approaches: Value of cytology as an adjunct to cystoscopy. Why it is still preferred despite new cell-based bladder tumor markers.

Possible authors: Dr. Murphy + Eva Wojcik

6. Bladder tumor marker (Urine markers for bladder cancer diagnosis):

Currently, the detection of primary and recurrent tumors is based on urine cytology and cystoscopy. With the high rate of recurrence, cystoscopies are regularly repeated with the aim of halting progression of the disease. For patients, this process is fraught with anxiety, pain and high cost. Therefore, intense work is being done to bring accurate bladder tumor markers into clinic for both the initial diagnosis and detection of tumor recurrence. The possibility of identifying a marker that could non-invasively differentiate benign and malignant causes of hematuria, and identify recurrences prior to their clinical manifestation is the objective of this area of research. In addition, due to the ease of obtaining voided urine specimens, bladder cancer is at the forefront of developing cancer diagnostic tests. In this review we will discuss many of the widely used or tested markers, along with some novel modalities. Background details will be provided as to themechanism of detection of malignant cells, the results of recent trials, and future directions of study. The next few years will no doubt bring newer markers and perhaps the elimination of others. Studies continue to refine the role of these markers in clinical practice but their ultimate efficacy will need to be borne out in large-scale clinical trials in a multitude of settings.

Confirmed authors: Shirodkar and Lokeshwar

7. Economics of bladder cancer diagnosis and surviellance: Cystoscopy is still the gold standard for both detection and surveillance of bladder cancer. Because of the cost involved in surveillance, and the treatment of recurrent tumors bladder cancer is one of the costliest cancer to treat. Several studies on cost analyses have shown that bladder tumor markers may prove to be cost effective however patients are reluctant to forgo cystoscopy. Thus, a discussion of cost versus benefits of both cystoscopy and bladder tumor markers will be helpful, given the number of bladder tumor markers currently in the market and more coming down the pike. Topics to be covered: Comparison of bladder cancer diagnosis in terms of cost and of tumor markers and analyses of cost versus benefits.

Possible authors: Marco Grasso Department of Urology, Milano Italy + Anulf Stenzl

Or Lotan

7. Prognostic Markers for bladder cancer:

Prognostic markers for bladder cancer are needed for monitoring treatment response after TURBT, TURBT+ intravesical therapy or cystectomy. Monitoring of treatment response is required for predicting recurrence, disease progression (from non-muscle invasive disease to muscle invasive disease, or from muscle invasive bladder cancer to metastasis) and survival. Several prognostic markers have been studied. Possible topics: markers in various cellular categories (cell surface, proliferation antigens, growth factors/growth factor receptors, nuclear antigens/transcription factors) with emphasis on p53, Ki67, pRb.

Possible authors: Fred Witjes from Nijmegen, The Netherlands + Habuchi, Japan

8. Molecular Nomograms for predicting prognosis and treatment response:

Recent investigations have shown that instead of single markers, molecular analysis of tumor tissues may allow better prediction of prognosis. Some of these advances include COXEN analyses, Forerunner genes. Topics to be included: cDNA microarray, microRNA, COXEN.

Possible author: Dan Theoderescu, University of Virginia, VA

9. Clinical management of Low-grade bladder tumors Treatment and Follow-up

TURBT, follow-up for recurrence (how often).

Topics to be included: Cystoscopy, Transurethral resection of low-grade bladder tumors.; Bladder and prostatic urethra biopsies; Second resection; Follow-up of patients with low-grade bladder tumors; Predicting recurrence and progression in TaT1 tumors

Possible authors: Osterlink + Hanus (Prague)

11. Intravesical Chemotheray: When appropriate, what is the treatment (e.g., mitomycin, thiotepa, adriamycin? Epirubicin?) Mechanism of action, dosing, efficacy, how to monitor efficacy, side effects. Any special consideration for CIS? Guidelines??

One, immediate, post-operative intravesical instillation of chemotherapy; Optimizing intravesical chemotherapy (EMDA); Definition of treatment failure

Possible author: Dr. Soloway

12. Intravesical Immunetherapy: BCG

Molecular basis of BCG treatment, when to give BCG, type strains (historical perspective and current status), BCG maintenance therapy, benefits of BCG (to inhibit progression to muscle invasion, recurrence, any survival benefits?), BCG toxicity, BCG failure (when and why?); The optimal BCG schedule; The optimal BCG dose;

Possible authors: Hemstreet OR Andreas Boehle

13. Cystectomy for non-muscle invasivebladder cancer

Patients with pT1 G3 bladder tumors are at high risk of tumour progression and death from disease. Induction and maintenance of intravesical BCG treatment has proven to reduce tumour progression in non muscle invasive bladder cancer at moderate risk of progression. However, recent data on survival and new developments in molecular markers and nomogramms predicting the clinical course of the disease often predict the then observed clinical scenario. Therefore some surgeons support an early radical surgical approach even in non muscle invasive disease classified as pT1, G3 or with a high risk profile (multiple tumours, tumour size, CIS, early recurrences, etc.). The pro- and con- for radical surgery should be discussed as well as an overview on the available published literature.

Confirmed authors: Axel Merseburger and Markus Kuczyk

14. Radical surgery

Indications: Radical cystectomy is the standard treatment for localized muscle invasive bladder cancer in most countries. There is still controversy about age, radical cystectomy and the type of urinary diversion. Cystectomy is associated with the greatest risk reduction in disease-related and non-disease related death in patients older

than 80 years. Traditionally radical cystectomy is recommended for patients with muscle-invasive bladder cancer T2-T4a, N0-Nx, M0, as well as extensive papillary disease that cannot be controlled with TUR and intravesical therapy alone.

Optimal timing and delay of cystectomy: In a retrospective series of 153 patients with a clear indication for radical surgery of locally advanced bladder cancer, a delay of treatment beyond 90 days of primary diagnosis caused a significant increase in extravesical disease (81 vs. 52%)

Technique and extent: Radical cystectomy includes the removal of the bladder and adjacent organs, that is prostate and seminal vesicles in men, and uterus and adnexa in women. Radical cystectomy also includes the dissection of regional lymph nodes. There is a substantial amount of literature about the extent of lymphadenectomy. Yet, data regarding its clinical significance are controversial. Laparoscopic cystectomy has been shown to be feasible both in male and female patients.

Arnulf Stenzl or e.g. Jürgen Geschwend, or Sudhir Rawal from India

15. Urinary Diversion

From an anatomical standpoint three alternatives are presently used after cystectomy: Abdominal diversion such as ureterocutaneostomy, ileal or colonic conduit, and various forms of a cutaneous continent pouch; Urethral diversion which includes various forms of gastrointestinal pouches attached to the urethra as a continent, orthotopic urinary diversion (neobladder, orthotopic bladder substitution; Rectosigmoid diversions, such as uretero(ileo-)rectostomy.

Debilitating neurological and psychiatric illnesses, limited life expectancy, and

impaired liver or renal function as well as TCC of the urethral margin or other surgical margins are contraindications to more complex forms of urinary diversion.

All used urinary diversions forms should be described with modern mortality and morbidity data. Aside a subchapter should cover the reachable disease-free and overall survival data.

Confirmed: Stefan Hautmann; Richard Hautmann (possible co-author)

16. Laparoscopic cystectomy:

Decision open versus laparoscopic cystectomy (who are the best candidates), benefits and pitfalls, long term results (??). The cystectomy itself and the subsequent urinary diversion can be done hand-assisted, robot-assisted or unaided. With the currently available technology and when using intestinal segments for the urinary diversion, to date a majority of authors favour an extracorporeal approach. There are no data confirming or declining benefits of laparoscopic cystectomy for the patients’ quality of life, tumour specific and overallsurvival.

Possible author: Indebir Singh Gill

17. Neoadjuvant chemotherapy:

Neoadjuvant chemotherapy is given to improve the outcome of cystectomy. Current regimen includes cisplatin and gemcitabine combination. Advantages of neoadjuvant chemotherapy will be a pT0 disease at cystecomy, failure of the treatment can lead to disease progression. Topic to be covered: Who are the candidates for neoadjuvant chemotherapy, types of neoadjuvant chemotherapy (platins +/_ gemcitabine), outcome, failure, any molecular markers that predict response to neoadjuvant chemotherapy.

Armir Sherif

18. Bladder cancer treatment and quality of life issues:

Patients undergoing bladder sparing treatment need to undergo frequent cystoscopy for surveillance, TURBT +/- intravesicle therapy for recurrent tumors. Patients with cystectomy and urinary diversion deal with an illeal conduit (and are at a risk for developing infections) or a neo-bladder. Thus, bladder cancer treatments pose certain quality of life issues for the patients and these may need to be considered when weighing benefits and cost of each treatment.

Sofi Fossa (EU guidelines/Oslo Norway)

19 Upper tract tumors: Diagnosis and Treatment.

Endoscopic and radiologic imaging for upper tract tumors. Value of cytology in monitoring upper tract tumors. Treatment? Laparoscopic versus open nephroureterectomy???

Prof. Oliver Hakenerg, Rostock Germany

Mesut Remzi from Vienna, Austria

20. Chemotherapy for metastatic bladder cancer:

Single agent: Cisplatin, carboplatin, taxanes, gemcitabine, (historic perspective, randomized trials, if any, doses, side effects, outcome), Combination therapy: MVAC, MVAC versus cisplatin, Gemcitabine + cisplatin: Discussion of randomized trials, dosing, toxicity, outcome. "Unfit" patients, second line therapy, tyrosine kinase inhibitors

Possible authors: Maria De Santis from Vienna, Austria

21. Bladder conserving treatment in muscle-invasive bladder cancer

Single agent, combination with chemotherapy, who is a candidate, randomized trials, efficacy, toxicity?

Possible authors: M. Milosevic, M. Gospodarowicz and Zietman

22. Non-TCC tumors: Diagnosis and treatment.

This chapter should cover the forms and treatment regimens for non-TCC tumours including chemotherapeutic regimens in case of systemic disease. Which tumors can be resected by TUR-B, where is a radical surgical procedure necessary? What is the optimal follow-up.