1. GENERAL INFORMATION
1.1.1 Incidence and mortality
In Europe, cancer of the bladder is the fourth most frequent cancer among men (Ferlay 2001), accounting for about 7% of the total cancers. There are an estimated 136,300 new cases each year (Ferlay 2001). The annual incidence rate is 32/100,000 in men and 9/100,000 in women while the annual mortality rate is 9/100,000 (11 for men, 4 for women) (Ferlay 2001). Some 70% of patients with bladder cancer are over 65 years of age. In men, the incidence by age rises rapidly from 1 per 100,000/year in patients less than 45 years old to 25 per 100,000/year in the age group 45-64, thereafter increasing at a reduced rate (87 per 100,000/year for ages 65-74 and 129 per 100,000/year for those older than 75 years of age) (Ferlay 1999). Bladder cancer incidence is either rising moderately or is steady in most developed countries (Stewart 2003). In England and Wales, incidence in men was increasing by about 2% every five years up to the end of the 1980s, and more quickly in women (6-7%); mortality in men fell by about 1% a year during the 1980s (Coleman 1999). There were about 49,000 deaths from bladder cancer in the European countries (Ferlay 2001). In Italy, bladder cancer incidence increased in both sexes (Zanetti 2004). The increase is mainly evident in the old age group (>65 years of age). By contrast, the mortality rates showed a statistically significant decrease in both sexes. The decrease in mortality rates is present in all age groups.
Prevalence of bladder cancer, that is the number of people living with a diagnosis of bladder cancer, is known for Italy (Micheli 1999). In 1992 the proportion of prevalent men was 477 per 100,000 and for women 92 per 100,000. The 5 year prevalence, that is the number of living people with a diagnosis of bladder cancer made 5 or less years before the index date, was 113 per 100,000. The last figure provides indications regarding the need for clinical follow-up and treatment for recurrences.
In Europe (Berrino 2003), during the period 1990-94, relative survival rates at 5 years after diagnosis of cancer of the bladder was 69% (70% in men and 67% in women). Five-year relative survival decreased markedly with age from 90% to 61% from the youngest (15-45 years) to the oldest age group of patients (75 years and over). Although the incidence of bladder cancer in men is higher than in women, survival was higher in men. This is one of the very few cancers for which survival is better in men than in women. Men seem to be diagnosed earlier for bladder cancer than women (Mungan 2000). It has been suggested that this is due that the male bladder is characterised by the higher pressure in the male bladder due to longer urethra, thicker detrusor muscle, and presence of prostate; which would hinder blood perfusion and metastatic spread. Furthermore, the circular muscle at the neck of the bladder is weaker in females and this may facilitate lymphatic drainage.
There are major differences between European countries in survival for patients with bladder cancer. Some Eastern European countries such as Poland, Estonia and Slovenia have been characterized by low 5-years relative survivals (less than 45%). In some Northern European countries (Iceland, Sweden, Finland, Norway), Germany, Austria and the Netherlands survival has been generally higher (more than 70%). An association between social deprivation and survival has been found for cancer of the bladder (Coleman 1999). Survival is higher for affluent men and women. This pattern is largely consistent at 1, 5, and 10 years after diagnosis and for men and women diagnosed in the 1970s and the 1980s. The deprivation gap between affluent and deprived groups (7 at 5 years after diagnosis) was similar and statistically significant in 6 English areas studied. The survival data reported in was derived from information collected by population-based cancer registries.
1.2 Aetiology and Risk Factors
1.2.1 Aetiologic factors
Tobacco smoking is responsible for approximately 65% of male cases and 30% of female cases of bladder cancer in population of developed countries (Brennan 2000). The risk associated with tobacco smoking is likely to be due to the presence in the smoke of aromatic amines including benzidine, 4-aminobiphenyl, 2-naphthylamine and 4-chloro-ortho-toluidine. Occupational exposure to industrial carcinogens in rubber, organic dye and metal refining and specifically occupational exposure to aromatic amines are correlated with a high risk of bladder cancer. The risk attributable to work-place exposure ranges from 10-20%. Cyclophosphamide, alkylating agent has been strongly and consistently linked to bladder cancer. Non-Hodgkin lymphoma patients treated with cyclophosphamide therapy have a dose-dependent increased risk of bladder cancer. Schistosomal infection plays an important role. This infection is responsable for about 10% of bladder cancer cases in the developing world and about 3% of cases overall (Pisani 1997). The areas principally affected are Iraq, Egypt, and South East Africa. In these areas Schistosoma eggs are found more frequently in association with squamous-cell than transitional-cell cancers (Tomatis 1990). Diet high in vegetables and fruits probably protect against bladder cancer (WCRF & AICR 1997).
1.3 Early Diagnosis
1.3.1 Screening and case finding
Screening may be performed by urinary cytology. Early diagnosis programs were suggested for populations at high risk (heavy smokers, occupational exposed) or in the elderly population, but there is no evidence in favour of its effectiveness (Saad 2001).
Referral of bladder cancer patients to specialized institutions is generally recommended. Inclusion in prospective trials can be discussed with those patients who meet the eligibility criteria under the following circumstances:
1. Evaluation of new agents for prophylaxis in recurrent superficial tumours
2. Evaluation of new agents or combination chemotherapy for locally advanced and metastatic disease.
2. PATHOLOGY AND BIOLOGY
2.1 Biological data
Seventy-five percent of bladder cancers are superficial at initial presentation; limited to the mucosa, submucosa, or lamina propria. Recurrence rates after initial treatment are 50-80%, with progression to muscle-invading tumours in 10-25%. For superficial disease, prevention of recurrence and progression are the primary issues. In muscle-invading bladder cancers, there is a 50% risk of distant metastases. It is important to identify those tumours that are biologically aggressive and that have the potential to result in mortality (Maffezzini 1998).
2.1.2 Tumour Growth
Bladder cancer is heterogeneous, with papillary, well-differentiated, non-invasive tumours contrasted with sessile, poorly differentiated, invasive cancers. Carcinogens produce lesions in the genome of urothelial cells which initiate the process of carcinogenesis. This appears to occur in a sequence. Multiple lesions are required to cause malignant transformation. Recognizable lesions are the most obvious aspect of the process, but the urothelium is continually at risk for the development of new lesions (Jones 1993; Sandberg 1994).
2.1.3 Genetic abnormalities
The role of oncogenes is under intense investigation. Cytogenetic analysis has provided strong evidence that loss of a suppressor gene or genes on chromosome 9 are frequently involved in the genesis of bladder cancer. Mutations of the p53 tumour suppressor gene have been identified in 50% of high grade and stage bladder tumours, and may be important in determining survival after neo-adjuvant chemotherapy, on a type 3 level of evidence (Jones 1993; Schultz 1994). Oncogenes of the ras gene family have been found in bladder cancer. A correlation has been shown between the expression of ras protein and high histological grade. In addition, an association between c-myc oncoprotein expression and recurrence or invasion in superficial tumours has been shown. Methylation of the c-myc oncogene may also correlate with stage and grade. Newer and increasingly important prognostic indicators may be utilized to select patients who may benefit from chemotherapy. In the context of well-conducted clinical protocols, investigational prognostic factors such as DNA ploidy, p53, mdr 1, retinoblastoma gene product, NM23 RNA levels, and T138 surface antigen expression may be used to select patients for specific therapies. Evaluation of drug resistance, DNA content, expression of epidermal growth factor receptor, chromosome abnormalities, oncogene expression, and angiogenesis are all investigational. Currently, the conventional hystopathological assessment of grade and stage allows for only a gross stratification of clinical outcomes for patients with bladder cancer. Despite significant research in the molecular understanding of neoplasia, the promise of accurate predictions of tumour behaviour based on molecular markers has yet to be realized. Recent development of techniques to evaluate tumours for expression of a myriad of genes simultaneously in multiple tissue sites(microarrays), with linkage to clinical outcomes isi still investigational (Buscarini 2005).
2.1.4 Flow Cytometry
Flow cytometry may be helpful in staging and planning treatment of patients with bladder cancer, but is rarely used with the exception of some specialized academic centers. There appears to be a strong correlation between DNA content or ploidy and the level of differentiation (tumour grade), depth of invasion (tumour stage), and response to chemotherapy. Flow cytometry correlates with chromosomal changes. Progression and recurrence of tumours correlate with aneuploidy and an increase in the proliferative rate (Hermansen 1988). The role of flow cytometry in the diagnosis and assessment of response should be considered investigational.
2.1.5 Genetic Abnormalities and Prognosis
Patients who are non-responders, and those with subsequent disease progression have been shown to overexpress the multidrug resistant gene (mdr) and p-glycoprotein. This may be in part responsible for the failure of chemotherapeutic regimens such as M-VAC or CMV. Molecular probes which define drug resistance are still investigational (Fojo 1987). Mutations of the p53 tumour suppressor gene on chromosome 17 have been identified in half of all high grade, high stage bladder cancers (Jones 1993). p53 appears to have prognostic value for survival in invasive bladder cancers treated with neo-adjuvant chemotherapy (Bajorin 1994). Other recently described markers such as collagenase and autocrine motility factor may be associated with cancer progression. The presence of receptors for epidermal growth factor or transferrin may also reflect an adverse prognosis (Liotta 1988). Reduced expression of p27 Kip1 and cyclins D and E correlate with increased grade, stage and mortality in bladder cancer (Del Pizzo 1999). Several groups have reported data suggesting that low p27 expression with or without low cyclin E expression portends an adverse prognosis in bladder cancer (Kamai 2001). Decreased p27Kip1 expression is prognostic in several cancers, including breast, prostate and non small cell lung cancer, and is usually associated with increased cyclin E expression. Juan et al (Juan 2001) recently described disruption of the nucleoplasm-nucleolar shuttling of cyclin E in bladder cancer cell lines, suggesting that altered intranuclear localization of cyclin E rather than overexpression may be a distinguishing feature of progressive bladder cancer. Overexpression of a low molecular weight cyclin E was recently reported to be a major prognostic factor in breast cancer. Interestingly, loss of p27Kip1 expression in superficial bladder cancer correlates with disease recurrence and invasion, as does low expression of cyclin D1. Patients with low cyclin D1, low p27Kip1 and a high proliferative index measured by Ki67 expression had an extremely high rate of recurrence. Ploidy, vascularity, p53 status and other markers are considered of uncertain clinical benefit and should not be used to guide treatment decisions outside of the experimental protocol setting.
2.2 Histological Types
2.2.1 Incidence of histological types
More than 90% of urothelial tumours originate in the urinary bladder, 8% originate in the renal pelvis, and the remaining 2% originate in the ureter and urethra. In the Western world, the majority of bladder carcinomas are transitional cell carcinoma (TCC), while squamous cell carcinoma and adenocarcinomas account for 5% and 2% respectively. Adenocarcinomas may arise in the dome of bladder from a primary site in the urachus, but most often occur in the trigone. Squamous cell carcinomas are often associated with chronic irritation or infection. Squamous cell carcinoma of the bilharzial bladder differs from the bladder cancer seen in Europe and the United States. The distinct variants of squamous cell carcinomas, with diverse etiologies and biology, merit separate discussion (Sternberg 1996).
2.2.2 ICD-O Classification (ICD-O 2000)
Transitional cell carcinoma in situ (8120/2)
Transitional cell carcinoma (8120/3)
Squamous cell carcinoma (8070/3)
Small cell carcinoma (8041/3)
2.2.3 Transitional Cell Carcinoma
Transitional cell carcinomas (TCC) account for more than 90% of bladder cancers. An increase in the number of epithelial cells with formation of papillae, incomplete cellular maturation with loss of polarity, clumping of chromatin, and an increased number of mitoses are the most significant microscopic features. About one third of TCC may also contain squamous cell, spindle cell, or adenocarcinoma.
2.2.4 Carcinoma in situ
Carcinoma in situ (CIS) is suspected when a velvety spot, reddish color, is visible at endoscopy. Its microscopic appearance is of poorly differentiated flat, intraepithelial, TCC. It portends a poor prognosis. CIS is rarely associated with superficial, well-differentiated, bladder tumours and, when present, it confers higher recurrence rates. Conversely, it occurs in one fourth or more of patients with high grade, infiltrative disease. It may be asymptomatic, especially in the initial phases, and it most frequently may cause symptoms of bladder irritation. The natural history of CIS is not clearly understood.
2.2.5 Squamous Cell Carcinoma
A rather wide variability in the incidence of squamous cell carcinoma has been recorded. It represents less than 5% of all bladder cancers in the Western world, whereas in Egypt it accounts for up to 75% of cases. Almost 80% of these cancer are associated with chronic infection with S. haematobium resulting in “Bilharzial” bladder cancers. Nonbilharzial squamous cancers are associated with chronic bladder irritation, i.e. from long term indwelling catheters, urinary stones, or paraplegic bladders. At microscopy these tumours show squamous cells typically arranged in concentric aggregates forming squamous pearls with varying degrees of differentiation.
2.2.6 Adenocarcinoma and Urachal Carcinoma
Adenocarcinomas of the bladder are rare tumours, accounting for less than 2% of all bladder tumours. They may arise in the base of the bladder or in the dome. Adenocarcinomas may also arise in structures located outside the bladder, i.e. the urachus and are called urachal carcinomas. Metastatic adenocarcinoma may spread to the bladder, from breast, gastric, or rectal cancer. This represents a more rare form of bladder tumour. The prognosis of primary bladder adenocarcinoma is generally poor. They do not respond well to chemotherapy, and surgery, when feasible, represents the mainstay of treatment (Sternberg 1996).
2.2.7 Co-existence of different histological types
The co-existence of different histological types of cells is observed in some cases. Most frequently flat carcinoma in situ is associated with muscle infiltrating transitional papillary tumours. Islands of squamous cell carcinoma or, less commonly, adenocarcinoma may also be found in infiltrating disease. They generally indicate a worse prognosis.
2.2.8 Tumour Grading
Tumour grading must be included in the pathological report of the transurethral resection of bladder (TURB) and the surgical specimen. It is considered to be predictive of the biological behaviour of the disease.
Gx Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3-G4 Poorly differentiated or undifferentiated
Currently, there is a growing interest in defining grading into only two distinct categories: Low Grade and High Grade. This may help in dividing the population of patients according to Low and High Risk.
2.3 Accuracy and reliability of pathological diagnosis
2.3.1 The pathology report
The pathology report should include a description of the histological type, or types if more than one neoplasm is present in the specimen. The following features should also be described in the samples obtained at the TURB a) grade, b) extent of infiltration observed in the underlying tissues, (i.e. muscularis mucosae, lamina propria, muscular tissue, etc.) c) amount of muscular tissue present in the specimen, d) presence of cancer cell clusters within vascular and or lymphatic vessels. The pathology report after cystectomy should include: e) the number and size of the lesion(s), f) the architecture of the lesion(s) (i.e. papillary, sessile, flat), g) the pattern of infiltrative growth (i.e. dendritic, “pushy margins”, etc.), h) the presence and extent of cancer tissue in the perivesical fat or adjacent structures included in the specimen (prostate or uterus), i) the presence of foci of CIS in the mucosa of the bladder and in the terminal portion of the ureters.
2.3.2 Histopathological examination
Pathological diagnosis and staging represent the cornerstone upon which treatment decisions are based. Cold cup biopsies alone may permit definition of the hstological type and grade of the specimen. However, this type of specimen, may not be representative of the histology and grading of the entire lesion. TURB, in contrast, provides more material for the pathologist. It is crucial that tissue samples obtained at TURB are collected separately and sent to the pathologist as superficial, or endoluminal portion of the tumour, and deep, or full thickness muscular layer underlying the tumour, to allow the most accurate definition of pathologic stage.
3.1 Diagnostic signs and symptoms
Vesical irritation alone can be the only presenting symptom and may indicate CIS. Less commonly, a urinary tract infection with urinary urgency is the presenting symptom. Patients with advanced bladder cancer may present with pelvic pain due to an enlarging tumour or nerve root compression. Ureteral obstruction may be asymptomatic or cause flank pain. Lower extremity edema may be the result of lymphatic or venous obstruction. In the rare patient who presents with metastatic disease, bone pain may be the predominant symptom.
Hematuria is the most frequent reason for seeking medical advice. Bladder cancer can, however, mimic urinary tract infection or prostatism. In an adult, especially over 50 years of age, with asymptomatic gross hematuria, microscopic hematuria, or irritative voiding symptoms, it is recommended that the diagnosis of bladder cancer is considered.
3.2 Diagnostic strategy
3.2.1 Clinical assessment and imaging
Sonography is frequently employed in the initial diagnostic strategy, although in the presence of gross or microscopic hematuria, an IVP (intravenous pyelogram) or a CT scan of the abdomen and pelvis with contrast is often indicated. The entire urothelium should be visualized from the renal pelvis to the bladder. Urothelial tumours appear as filling defects within the urinary tract, most frequently within the bladder. An IVP can depict indirect signs of infiltration of the bladder wall, i.e. asymmetry of the bladder image at full capacity, or hydronephrosis and ureteral enlargement. Diagnostic endoscopy (cystoscopy) usually follows the radiological studies. The macroscopic appearance, location, number, and growth pattern (papillary, sessile, nodular, or flat) of the lesion(s) can be estimated and a biopsy taken for histological diagnosis. Urothelial tumours exfoliate cells in the urine. Therefore, cytology of the first voided morning urine sample, or one obtained by bladder lavage at cystoscopy may be helpful, especially in the diagnosis of lesions with poorly defined macroscopic appearance (i.e. carcinoma in situ). Recently, Fluorescent in situ hybridisation (F.I.S.H.) of voided urine has demonstrated improved sensitivity over cytology in such instances (Sokolova 2000; Bubendorf 2001). CT scans of the abdomen and pelvis have gained wide popularity, although their accuracy in delineating local tumour extension within the bladder wall is less than optimal and understaging and overstaging may occur in up to 50% of cases. NMR imaging hasn’t offered a clear advantage over CT scans. Imaging studies such as CT scans and NMR, can show the presence of lymph node enlargement or metastases at visceral sites (i.e. liver). A chest x-ray and a bone scan are usually recommended in the evaluation of patients with muscle-invasive disease to detect lung or skeletal metastases, respectively.
3.2.2 Pathological diagnosis
A pathological diagnosis may be obtained by performing cold cup biopsies at cystoscopy. This provides information about the histological type and grade of the lesion, however, it does not constitute a significant step forward in patient management since a TURB is required for this purpose.
4.1 Staging Classification
4.1.1 Formal stage classification
There are two staging systems which are primarily used for bladder cancer; the TNM system (UICC 2002) and the Jewett-Marshall-Strong system. The TNM system is more descriptive and accurate and is currently preferred. A description of both systems follows.
4.1.2 TNM Staging classification
Primary Tumour (T)
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ “flat tumour”
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscle
pT2a Tumour invades superficial muscle (inner half)
pT2b Tumour invades deep muscle (outer half)
T3 Tumour invades perivesical tissue
pT3b Macroscopically (extravesical mass)
T4 Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall, or abdominal wall
T4a Tumour invades the prostate stroma, seminal vesicles, uterus, or vagina
T4b Tumour invades the pelvic wall or abdominal wall
Regional lymph nodes (N)
Regional lymph nodes are those within the true pelvis; all others are distant lymph nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node, 2 cm or less in greatest dimension
N2 Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in dimension
N3 Metastasis in a lymph node > 5 cm in greatest dimension
Distant Metastasis (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
|Any T||Any N||M1|
GX Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3-G4 Poorly differentiated or undifferentiated
4.1.3 Jewett, Marshall, Strong Classification
Stage 0: No tumor found in the specimen superficial tumour not invading the submucosa carcinoma in situ
Stage A: superficial tumour invading the submucosa
Stage B: muscle invasive tumour, further specified in
Stage B1: superficial invasion (less than halfway)
Stage B2: deep invasion (more than halfway)
Stage C: invasion into the perivesical fat
Stage D: Extra vesical disease, further specified in
Stage D1: invasion of contiguous organ or regional lymph nodes metastases
Stage D2: Extra regional lymph nodes
metastases or metastases to distant organs.
4.2 Staging procedures
Imaging techniques are generally of little help in staging the local extension of bladder cancer. CT scans of the abdomen and pelvis have gained wide popularity, although their accuracy in delineating local tumour extension within the bladder wall is not optimal. Understaging and overstaging may occur in some 50% of cases, therefore, is not recommended for this purpose. NMR does not offer a clear advantage over CT scans. Imaging studies, however, can show the presence of lymph node enlargement or metastases at visceral sites (i.e. liver). A bone scan and a chest x-ray or CT scan are usually recommended in the evaluation of patients with infiltrative disease to detect lung or skeletal metastases.
4.2.2 Transurethral resection
TURB, is mandatory to obtain an accurate pathological diagnosis and staging of the primary lesion. TURB is performed under general or regional anesthesia. It implies the removal of both the endoluminal portion of the lesion and biopsy of the underlying detrusor muscle of bladder. Specimens should be labeled and sent separately to the pathologist (i.e. endoluminal portion, inner muscular wall, deep muscular wall and perivesical fat). This permits the pathologist to define the depth of invasion and the precise staging category. During transurethral resection, the surgeon should attempt to remove the entire lesion, reaching until the perivesical fat, except in lesions adjacent to the course of the obturatory nerves or in the bladder dome (to avoid contraction of the obturator muscle and possible perforation of the bladder into the peritoneal cavity, respectively). Large volume lesions are not always amenable to a complete TURB. In such cases a partial or incomplete TURB is performed, with the intent of obtaining full thickness tissue samples of the tumour and underlying bladder wall for appropriate staging. Transurethral laser ablation is sometimes employed for small lesions. However, it does not allow adequate tissue sampling. Transurethral fulguration should be discouraged since it is of no value for staging purposes. Repeat-TURB must be considered in cases of incomplete resection and when the pathology report describes only superficial disease, as well as in cases of incomplete resection due to the number, or the size, or the location (i.e. anterior bladder wall) of the lesions. ,Klan et al reported residual disease in more than one third of cases (Klan 1991).
5.1 Natural history
5.1.1 . General considerations
Whereas Ta and T1 lesions are generally characterized by a good prognosis and low lethal potential, CIS is generally more aggressive. Superficial bladder cancers, Ta and T1 are generally low grade. They rarely become invasive, but recur locally in approximately 50%-70% of patients within 6-12 months. The risk of progression is related to grade and stage. The rate of progression for grade I is approximately 2%, 11% for grade II, and 45% for grade III. Approximately 4% of Ta tumours progress, compared to 30% of T1 tumours. Combining histological grade, G, with primary tumour stage, T, the risk of progression rises to approximately 50% for G3 T1 tumours (Mulders 1994). The most important prognostic factors are the number of tumours at presentation, and recurrent disease at the the first 3 month cystoscopy (Parmar 1989). Five year survival rates after radical surgery for muscle invasive disease are generally poor. They may vary from 40 to 60% for stage pT2 N0 M0 disease to 10% for stage pT4. The probability of nodal metastases in association with muscle infiltrative disease is 15 to 25%. Survival for patients found with nodal metastases at the time of surgery may vary from 6 months to 2 years. Some authors have observed a correlation of survival with the lymph-node dissection extent and have proposed the concept of “node-density”. Node density is a surgical concept that relates to the ratio of positive nodes on the total number of nodes harvested at cystectomy. Patients with a node density ratio of 20% (Herr 2003). Predictors for relapse after cystectomy include depth of invasion, involvement of adjacent viscera (perivesical fat, vascular invasion, prostate, vagina), and the presence of nodal metastases. Recurrence is related both to stage and nodal status. High grade, high-stage (pT3b-4) tumours frequently (40-60%) are found to have lymph node involvement (pN+) at radical cystectomy. Although 5-year survival for patients with muscle invasive bladder cancer is approximately 50%, for those patients at higher risk with pT3-pT4 and/or pN+ M0 bladder cancer, 5-year survival after radical cystectomy is only 25%-35% (Vieweg 1994; Sternberg 2002a).
5.1.2 Prognosis of Superficial Bladder Cancer (Ta – T1)
Whereas Ta and T1 lesions are generally characterized by good prognosis and low lethal potential, CIS is generally (can be) more aggressive. Superficial bladder cancers, Ta and T1, are usually low grade. They rarely become invasive, but recur (locally) in approximately 50% of patients within 6-12 months. The risk of progression is related to grade and stage. The rate of progression for grade I is approximately 2%, 11% for grade II, and 45% for grade III. Approximately 4% of Ta tumours progress, compared to 30% of T1 tumours. Combining histological grade, G, with primary tumour stage, T, the risk of progression rises to approximately 50% for G3 T1 tumours (Mulders 1994). The most important prognostic factors are the number of tumours at presentation, and recurrence of disease within the first 3 months of follow-up (Parmar 1989; Allard 1998).
5.1.3 Carcinoma in situ (Cis)
CIS is a flat, non-papillary, non-invasive, anaplastic epithelium closely resembling high-grade TCC. It is considered to represent the earliest stage in the evolution of invasive bladder cancer: it represents a frequent finding in cystectomy specimens, in association with muscle infiltrative cancer. The presence of CIS has been associated with an increased risk of subsequent progression and the capability to evolve to muscle invasion represents its most worrisome potential evolution. This can be observed in more than 50% of the cases in the absence of BCG treatment (Lamm 1992). There are no clear data on survival of patients with pure CIS, because of the relatively rarity of the condition and the variety of treatments employed.
5.1.4 Prognosis of muscle infiltrative disease (T2 – T4)
Five year survival rates after radical surgery for muscle invasive disease are generally poor. They may vary from 40 to 60% for stage pT2 N0 M0 disease to 10% for stage pT4. The probability of nodal metastases in association with muscle infiltrative disease is 15 to 25%. Survival for patients found with nodal metastases at the time of surgery may vary from 6 months to 2 years. Some authors have observed a correlation of survival with the lymph-node dissection extent and have proposed the concept of “node-density”. Node density is a surgical concept that relates to the ratio of positive nodes on the total number of nodes harvested at cystectomy. Patients with a node density ratio of 20% (Herr 2003). Predictors for relapse after cystectomy include depth of invasion, involvement of adjacent viscera (perivesical fat, vascular invasion, prostate, vagina), and the presence of nodal metastases. Recurrence is related both to stage and nodal status. High grade, high-stage (pT3b-4) tumours are frequently (40-60%) found to have lymph node involvement (pN+) at the time of radical cystectomy. Current selected studies indicate a 15-20% 5-year survival after cystectomy in patients with nodal metastases, and 35-40% 5-year survival for patients with N1 tumours (Vieweg 1994). With direct invasion into adjacent viscera, cure is obtained in less than 10%. The strongest predictor of risk for later urethral disease is TCC involvement of the prostate (Montie 1994). Other known prognostic factors include: histology, grade, presence or absence of ureteral obstruction and the extent of surgical resection (Vieweg 1994; Montie 1994; Sternberg 1995a).
6.1 Treatment strategy
6.1.1 General Considerations
Treatment is defined according to the stage of disease, and depends upon whether the tumour is superficial or muscle-invasive. For certain patients one therapeutic modality is sufficient; for others a combined-modality approach is required. Surgery is the mainstay of standard treatment. TURB is the main surgical treatment for superficial disease, with or without intravesical therapy. Cystectomy (open surgery with removal of the bladder) and urinary diversion is the standard treatment for muscle invasive disease. Endovesical chemotherapy has been employed after endoscopic resection to prevent recurrences of superficial tumours. The most effective agent for both prophylaxis of disease recurrence and progression from superficial to invasive disease is BCG administered endovesically, on a type 1 level of evidence (Lamm 1995a; Lamm 1995b; Herr 1995). The accepted treatment for muscle infiltrative disease is radical cystectomy and in a few countries, radiation therapy. Radical cystectomy is considered as the gold standard of treatment, on a type C basis (Smith 1997). Technical refinements achieved in the last ten years in the field of continent urinary diversions, employing different segments of the gastrointestinal tract, permit a better quality of life to be achieved in the vast majority of patients. In locally advanced and metastatic disease, systemic chemotherapy can achieve clinical responses in approximately one half of the patients. In the past, the most commonly used regimens have included cisplatin, vinblastine, metothrexate and anthracyclines.
6.2 Superficial disease (pTa, pT1, N0, M0)
6.2.1 Treatment strategy
The aim in treatment of superficial disease is to eradicate lesions in the bladder with an endoscopic approach whenever possible. Intravesical treatment is given to prevent recurrences and hopefully prevent disease progression.
6.2.2 Transurethral resection (TURB)
TURB is indicated as the standard treatment on a type C basis, for superficial bladder cancer stages Ta and T1, NO, MO. It implies the removal of both the endoluminal portion of the lesion and the underlying detrusor muscle forming the bladder wall. The two specimens should be sent separately to permit the pathologist to define the depth of invasion and permit appropriate staging. Morbidity and mortality from this procedure are low. Although 5-year survival after TURB for superficial disease is relatively high, TURB alone can only achieve local control in about 30% of cases. This is due to the tendency of the disease to recur after the first episode in about 70% of patients (Heney 1983; Herr 1992). Superficial bladder cancers are usually low grade. They rarely become invasive, but locally recur in approximately 50% of patients within 6-12 months. The risk of progression is related to grade and stage (Heney 1983; Herr 1992). No therapy is recommended on a type C basis, for patients with low risk of recurrence, that is, patients with solitary stage Ta, grade 1-2 TCC. A single instillation of chemotherapy right after TURB is able to reduce the recurrence rate by about 50%, on a type 2 level of evidence (Oosterlinck 1993; Tolley 1996) and to reduce the need for maintenance therapy for intermediate risk tumours (Bouffioux 1995).
6.2.3 Intravescical treatment
The administration of intravesical chemotherapy or immunotherapy associated with TURB, with the intent of reducing the incidence of recurrences is recommended on a type C basis, for patients at significant risk of recurrence (Lamm 1995c; Cookson 1997). Immunotherapy with intravesical BCG can significantly reduce such risk. Moreover, intravesical BCG appears to be more effective than chemotherapy in the prevention of (recurrences and) progression, on a type 1 level of evidence (Lamm 1995a; Lamm 1995b; Herr 1995; Lamm 1995c). Among the chemotherapeutic agents, mitomycin C, Adriamycin, and epidoxorubicin are the most widely used. Among patients with recurrence, the risk of progression to infiltrative disease is about 10-15%. Intravesical therapy provides close proximity of the drug to the tumour, and avoids the toxicity of systemic therapy. For patients at intermediate risk (those with infrequent recurrence of grade 1-2, stage Ta tumour) no treatment or more often intravesical chemotherapy are considered as standard options on a type C basis (Heney 1983; Lamm 1995a ; Lamm 1995b; Herr 1992). Patients at high risk of disease progression (defined as those with CIS, grade 3 TCC, Stage 1 TCC, or positive post resection urinary cytology) should be treated with intravesical BCG, on a type 1 level of evidence (Herr 1995; Lamm 1995c; Cookson 1997). In randomized studies, the mean rate of progression is 14% for patients who receive BCG versus 28% for patients who do not receive BCG (Lamm 1995b; Herr 1995; Lamm 1995c).
Recently, it has been reported in a multicentric randomised trial, that the endovesical administration of a combined regimen using a cytostatic agent (MMC) in a hyperthermic micro.waves induced solution, is more effective for prophylaxis than MMC alone (Colombo 2003). Further studies are currently on-going.
6.2.4 Radical ystectomy
Radical cystectomy is recommended on a type R basis, for high risk patients with multifocal G3 or recurrent disease or in the presence of associated Cis. G3 T1 tumours are currently treated by immediate cystectomy or cystectomy at the first sign of recurrence.
6.2.5 Radiation therapy (RT)
TURB is considered the first treatment for Stage T1 lesions. When multiple lesions are present that cannot be controlled by endoscopic means and intravescical therapy, cystectomy is required . If cystectomy is contraindicated due to age or poor medical conditions, radiation therapy may be considered. Although the optimum tumouricidal dose level of radiotherapy is unknown, most recent series have recommended a dose of 6500 cGy, at daily doses of 180 to 200 cGy to the tumour region, with a restricted dose of 4750 to 5500 cGy to the whole bladder and perivesical region. The four field box technique is most often used. This encompasses the whole bladder, perivesical soft tissues, and the pelvic lymph nodes, while minimizing the dose to the rectum and anal canal. If treatment is delivered with fractions less than 200 cGy, toxicity is reduced (Fair 1993). After radiation, response is evaluated by cystoscopic examination. With RT alone, some 20-40% of patients are cured and preserve their bladder free of disease (Gospodarowicz 1992). At least 24% of patients have long term morbidity. Toxicities associated with RT include: decreased bladder function, cystitis, hematuria, and adhesions. Prognostic factors for local curability are absence of ureteral obstruction, papillary pattern of growth, and macroscopically, complete tumour resection by TURB prior to RT.
6.3 Carcinoma in situ (Cis, pTis)
6.3.1 Treatment Strategy
Treatment of carcinoma in situ consists of endovesical administration of agents, particularly BCG. CIS is a flat, nonpapillary, non-invasive, anaplastic epithelium high-grade TCC. The association of CIS with low stage, low grade tumours has been related to an increased risk of subsequent progression and muscle invasion. Intravesical BCG is the standard treatment of choice, on a type C basis, for CIS, producing complete response rates in 70% of cases. In one study, this complete response rate was increased to 87% with additional maintenance therapy (Lamm 1995d). This consisted of 3 weekly treatments every 6 months for 3 years. Such results are more likely to be obtained in unifocal CIS, whereas in multifocal CIS, persistence of disease after immunotherapy may be expected in about 50% of cases. For persistent CIS after BCG, radical cystectomy represents the standard option of treatment on a type C basis (Lamm 1995a; Lamm 1995b; Herr 1992). Attempts to repeat BCG treatment or to treat with Mitomycin-C may represent an individualized therapeutic option but is not usually recommended for patients who are suitable candidates for surgery. Several phase I-II studies are ongoing with intravesical gemcitabine. Gemcitabine (2′,2′-difluorodeoxycytidine) is a pyrimidine analog that exhibits antitumour activity against a variety of solid tumours. Recent studies have shown gemcitabine to produce robust response rates in patients with metastatic bladder cancer. In a phase I study intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising activity in treatment of superficial bladder cancer (Laufer 2003). In a phase II study of 27 patients with a marker lesion, intravesical gemcitabine achieved a 23% complete response with good tolerability (Serretta 2005). No type 1 level of evidence is available to propose intravesical gemcitabine as a standard option. For patients with no disease at the follow-up cystoscopy, whether one or two courses of induction therapy were administered, maintenance therapy is advised. This recommendation is not universal. Regardless of whether or not maintenance therapy is administered, patients with CIS should be followed at 3-month intervals with urinary cytology and cystoscopy for the first 2 years, and if no recurrences are documented, every 6 months in the third and fourth years and then annually.
6.4 Muscle infiltrative disease pT2, PT3-4, N0, N1, M0
6.4.1 Treatment strategy
TURB alone can represent both a staging and a curative procedure at the same time in highly selected patients whose disease is pathologically limited within the inner half of the muscular wall of the bladder. Criteria for selection include single, low grade lesions, absence of a previous history of TCC, and absence of involvement of the ureteral meatus. Radical cystectomy represents the standard treatment on a type C basis for muscle infiltrative disease. Response rates to combination chemotherapy regimens of up to 70% in patients with advanced metastatic disease have led to investigation of its use for locally invasive disease in combination with conventional modalities of treatment. The term “neo-adjuvant” indicates chemotherapy given before cystectomy or in some instances before definitive RT. It is considered suitable for individual clinical use on a type 2 level of evidence for patients with operable stages T2 -T3 N0 who wish to attempt a bladder sparing strategy (Herr 1998), or for patients at high risk of having micro-metastatic disease (T4a, N+ or M+) (Sternberg 2001a). The EORTC/MRC randomized study of neo-adjuvant CMV revealed a 6% survival advantage at 7 years when neo-adjuvant chemotherapy was given prior to surgery or radiation (Hall 2002). Another study from the Southwest Oncology Group (SWOG) has suggested a borderline survival advantage for neo-adjuvant chemotherapy (Grossman 2003). At a median follow up of 8.4 years patients who received neoadjuvant chemotherapy, cystectomy and adequate lymphoadenectomy had a significantly improved freedom form local recurrence (Dotan 2005). This has not been confirmed by a similar Italian study, and the significance of these findings have been questioned (Sternberg 2001c). Meta-analyses have suggested that there is a 5% (HR=0.86, 95% CI 0.77-0.95, p=0.003) absolute improvement in survival at 5 years and a 9% (HR= 0.78 95% CI 0.71-0.86,p < 0.0001) absolute improvement in disease-free survival in good performance status, young patients with a good creatiinne clearance who were treated with neo-adjuvant cisplatin containing combination chemotherapy (ABCMC 2003). Preoperative RT alone is not recommended on a type 2 level of evidence (Smith 1997) while the combination of preoperative concomitant chemotherapy and RT can be considered suitable for individual clinical use on a type 2 level of evidence (Coppin 1996; Kachnic 1997; Hellsten 1998).
6.4.2 Radical cystectomy
Radical cystectomy includes the removal of the peri-vescical fat, the bladder, prostate and seminal vesicles in the male patient, and the uterus and the ovaries in the female patient. Bilateral pelvic lymphadenectomy, that is, the removal of the external iliac,nternal iliac, and obturator lymph nodes is considered as part of radical cystectomy. It is uncertain whether pelvic lymphadenectomy has a curative effect. Recently however, some authors have observed a correlation of survival with the lymph-node dissection extent and have proposed the concept of “node-density”. Node density is a surgical concept that relates to the ratio of positive nodes on the total number of nodes harvested at cystectomy. Patients with a node density ratio of 20% (Herr 2003). Radical cystectomy is the gold standard of treatment for muscle infiltrating disease on a type C basis. The best results in terms of 5-year survival rates are obtained in patients with disease within the bladder wall, stage pT2, with up to 65% 5-year survival, whereas for patients with infiltration of the perivesical fat, stages pT3a and pT3b, survival rates are lower, approximately 40-50%, and below 20% for patients with stage pT4 disease (Richie 1992; Soloway 1994). The majority of patients with nodal metastases at surgery will experience disease failure, both local and distant, within 24 months from radical cystectomy. Urinary diversion has been obtained by simple ureterocutaneostomy or uretero-ilela-cutaneostomy. In the last two decades, continent orthotopic intestinal reservoirs have been developed. They are a more convenient form of reconstruction and have become the most widely adopted urinary diversion. The bowel segments used for reconstruction are taken generally from the terminal ileum; part of the stomach, or from the left colon (e.g. the sigma) (Studer 1997; Stein 1994). Refinements in surgical techniques have limited the incidence of complications and contributed significantly to quality of life issues. Preservation of the external urinary sphincter and detubularization of the intestinal wall are key points in maintaining daytime urinary continence, and in preventing ureteral reflux, respectively. Night time urinary continence is usually incomplete, due to fluid shifts to the bowel segment used for reconstruction and reduced muscular tone of the external sphincter. Metabolic complications, mainly consisting in mild impairment of the acid base equilibrium, may be observed at a distance, but are easily corrected by oral bicarbonate. Disease in the prostatic urethra is a criterion for exclusion from orthotopic bladder replacement. Such patients are candidates for heterotopic bladder reconstruction, with intestinal reservoirs that are generally obtained employing ileo-colonic bowel segments, taking advantage of the ileo-cecal valve as a continence mechanism. The afferent ileal limb is anastomosed to the abdominal wall (usually at the umbilicus) and the patient can then perform self-catheterization. Simpler forms of urinary diversion, such as uretero-ileo cutaneostomy (e.g. Bricker’s operation) or ureterocutaneostomy, are generally reserved to poor prognosis or poor surgical risk patients. In case of diffuse superficial tumours not amenable to TURB (i.e. those involving the anterior bladder wall or the dome) or characterized by multiple recurrences, not controlled by TURB, radical cystectomy may be indicated. Thermochemotherapy, that is, the combination of antitumoural agents (MMC), and microwave induced local hyperthermia have been investigated also, in this patients showing superior ablative activity in some cases (Colombo 1998). It has to be outlined, however, that understaging is quite frequent in spite of their superficial appearance. The specimen obtained at radical cystectomy may reveal a higher stage of disease than previously suspected in up to 35% cases (Amling 1994). Failure after radiotherapy may be an indication for salvage cystectomy. Surgery in such cases is aimed at controlling the symptoms of the primary tumour and seldom is curative. Complications, such as bowel obstruction, rectal injuries, lymphorrhea and wound infection are reported in some 40% of cases. Furthermore, the use of irradiated bowel for urinary diversion is contraindicated and a colon conduit or ureterocutaneostomy must be considered for patients who undergo salvage cystectomy.
6.4.3 Partial cystectomy
Since urethelial cancer is potentially multifocal and characterized by the tendency to recur over time, partial cystectomy is not generally employed as treatment for bladder cancer. A few phase II studies of partial cystectomy claim five year survival rates comparable to those of radical cystectomy. However, such observations have been made on retrospective series of patients and have not been studied in prospective clinical trials comparing partial cystectomy to radical cystectomy. Selected cases, such as in patients who represent a poor surgical risk or elderly patients with unifocal, low grade lesions, not involving the prostatic urethra, may be considered for partial cystectomy provided that the portion of bladder uninvolved by disease is large enough to maintain normal voiding function. Partial cystectomy has also been suggested on an investigational basis for patients with unifocal lesions following a response to neo-adjuvant chemotherapy (Sternberg 2003).
6.4.4 Neo-adjuvant (preoperative) chemotherapy
Neoadjuvant chemotherapy was intended for patients with operable clinical stage cT2 to cT4a muscle invasive disease. The rationale for giving chemotherapy before cystectomy or definitive RT is based on the intent to treat micrometastatic disease, present at the time of diagnosis. Neo-adjuvant chemotherapy was originally devised to eliminate micrometastases present at the time of diagnosis. It has also been used to determine response to chemotherapy using the bladder tumour as an in vivo marker. Neo-adjuvant chemotherapy is considered suitable for individual clinical use on a type 2 level of evidence for patients with operable stages T2 -T3 N0 who wish to attempt a strategy of bladder sparing surgery (Herr 1998), or for patients at high risk of having metastatic disease (T4a, N+ or M+) (Sternberg 2002b). Many single arm, non-randomized pilot studies have established the feasibility and safety of administering neo-adjuvant chemotherapy. Overall response rates of 40-70% with CR (complete remission) rates in the 30% range have frequently been reported (Sternberg 2002a). These trials have demonstrated that neo-adjuvant chemotherapy can produce tumour “downstaging.” Results from the Intergroup trial conducted by SWOG have been published (Grossman 2003). Patients with cT2 to cT4a were randomized between three cycles of neoadjuvant M-VAC chemotherapy and cystectomy or cystectomy alone. Enrollment took place over an 11-year period at 126 institutions and patients were stratified according to age (<65 years or ¡Ý65 years) and stage (cT2 versus cT3 or cT4a). Of the 317 patients entered, 307 were eligible. Eighty-two percent in the M-VAC group and 81% in the surgery group actually underwent cystectomy. Median survival was 77 months in patients who received neoadjuvant M-VAC as compared with 46 months in patients who underwent cystectomy alone. The results when initially presented were not statistically significant; however, in part due to what turned out to be a very long accrual period and follow-up, the results achieved borderline statistical significance (P = 0.06; two-sided stratified log rank test). There was a trend toward improved survival in favor of M-VAC-treated patients. The estimated risk of death was reduced by 25% (HR 1.33). The EORTC/MRC trial is the largest neoadjuvant randomized trial in the literature. This trial was performed more or less in the same time period as the SWOG trial. In this trial 976 patients were accrued over a 5 1/2-year period from 106 institutions. CMV neoadjuvant chemotherapy versus no chemotherapy was evaluated. Since this trial sought to be all-inclusive, definitive therapy was left up to the choice of the investigators and included cystectomy and RT. When published in 1999, there was a nonsignificant trend toward improvement in survival in patients on the CMV arm. In a 2002 ASCO update, with follow-up of 7.4 years, the data reached statistical significance (P = 0.048). There was a 5.5% benefit in favor of patients treated with CMV chemotherapy.Survival at 5 years was 50% compared with 44%, and at 8 years was 43% as opposed to 37% in the CMV arm. Although Hall concluded that there was no change in absolute benefit, patients treated with CMV had a consistent survival benefit that was maintained over time. An almost identical trial to the SWOG study was performed by the GUONE cooperative group in Italy. Two hundred six patients were randomized in a 6 1/2-year period to neoadjuvant M-VAC before cystectomy versus cystectomy alone.No clear differences in survival were demonstrated as 3-year survival was 62% for the M-VAC-treated patients and 68% for the cystectomy-alone arm. Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials (RCTs) involving over 3000 patients. A systematic review and meta-analysis of individual patient data to evaluate the effect of neoadjuvant chemotherapy on survival in patients with this invasive bladder cancer has been conducted. Platinum based combination chemotherapy showed a significant benefit on overall survival with a combined hazard ratio (HR) 0.86 (95% CI 0.77 to 0.95, p=0.003); 14% reduction in the risk of death; 5% absolute benefit at 5 years (95% CI 1 to 7%); overall survival increased from 45% to 50%. This effect was observed irrespective of the type of local treatment and did not vary between subgroups of patients. The HR for all trials, including those that used single-agent cisplatin, tended to favour neoadjuvant chemotherapy (HR= 0.89, 95% CI 0.81 to 0.98, p=0.022). Although platinum based combination chemotherapy was beneficial, there was no clear evidence to support the use of single-agent platinum, indeed there was significant difference in the effect between these groups of trials (p=0.029) (ABCOC 2005).
6.4.5 Neo-adjuvant radiotherapy or chemo/radiotherapy
Preoperative RT alone is not recommended on a type 2 level of evidence (Smith 1997) while the combination of preoperative concomitant chemotherapy and RT can be considered suitable for individual clinical use on a type 2 level of evidence (Coppin 1996; Kachnic 1997; Hellsten 1998). In some institutions, radiation therapy has been used in association with systemic chemotherapy as an integrated approach for bladder preservation (Shipley 2003). A randomized trial from the Canadian National Cancer Institute (Coppin 1996) showed significantly better local control (recurrence rate 40% vs 59%) by adding concomitant cisplatin and preoperative RT. However, the initial advantage in overall survival seen at 3 years was not confirmed at 6.5 years. As mentioned in section 6.4.4, a Scandinavian trial has confirmed a 20% survival advantage for patients treated with adriamycin, cisplatin and radiotherapy prior to surgery (Hellsten 1998). Attempts at bladder preservation should also evaluate the toxicity of these combined modalities. A definite assessment of such approach will require validation in prospective randomized trials. Most patients undergo TURB, followed by chemoradiation, restaging TURB, and then consolidative RT in responding patients or cystectomy in nonresponders. Five-year survivals between 42 and 63%, with organ preservation in approximately 40% of patients, have been reported. Although survival is similar to that in contemporary cystectomy series, the combined morbidity of chemotherapy and RT can be significant. The use of newer active chemotherapeutic agents such as gemcitabine and the taxanes in the neoadjuvant setting or as concomitant therapy with radiation remains experimental, but is being incorporated into treatment protocols. Neoadjuvant gemcitabine, paclitaxel, and carboplatin followed by observation or immediate cystectomy is being studied by the SWOG. Molecular markers, recurrence rates, and cystectomy-free survival are evaluated. As in the case with neoadjuvant chemotherapy alone, patients should be highly motivated to preserve their bladders and understand the possible side effects of combined therapy.
6.4.6 Adjuvant chemotherapy
There is no type 1 level of evidence of an advantage for adjuvant chemotherapy for treating muscle infiltrative disease (Sternberg 2005). Adjuvant chemotherapy is widely used after cystectomy in patients with pT3-pT4a and/or pN+ M0 disease in an effort to delay recurrence and prolong survival. This approach of giving chemotherapy after local treatment has led to increases in survival in patients with several other solid tumours. The rationale for giving adjuvant chemotherapy is that the local definitive treatment is performed immediately. Treatment decisions are based on pathologic criteria, after careful examination of the cystectomy specimen. Surgery is not delayed, and there is no time wasted for those patients who would not respond to chemotherapy. Micrometastases are treated when at a low volume. The advent of orthotopic bladder substitutions and the decreased morbidity of cystectomy has increased the tendency of urologists to operate early and then to consider adjuvant chemotherapy. There have been very few randomized trials evaluating adjuvant chemotherapy. Two studies have received attention. In an American phase III prospective trial, Skinner showed a significant increase in time to progression and survival in patients randomized to receive chemotherapy following cystectomy (Skinner 1991). This study has been criticized for its methodology and particularly for its improper subgroup analyses. In addition, the few patients who actually received chemotherapy received various different kinds of therapy (Stockle 1995). Patients were randomized to cystectomy or cystectomy followed by M-VAC or M-VEC. Patients had poor risk factors; 60% had positive nodes and most were stage T4. The study was prematurely discontinued with only a small number of patients after an interim analysis showed a benefit for patients randomized to chemotherapy. There was a 27% progression rate in treated versus 82% progression in control patients. Survival was different between the two groups as well since relapsing patients were not offered chemotherapy at the time of relapse. Five-year progression-free survival was 59% after the recommendation to receive chemotherapy versus 13% after recommendation to receive cystectomy alone. Due to the difficulty in interpretation of these adjuvant chemotherapy trials, a systematic review of published randomized trials of adjuvant cisplatin-containing combination chemotherapy in locally advanced bladder cancer was undertaken. Although these trials appear to show a difference in favor of adjuvant chemotherapy, serious methodological flaws were found. Major deficiencies were found in sample size, early stopping of patient entry, statistical analyses, reporting of results, and drawing conclusions (Sylvester 2000). The trials provide insufficient evidence to support the routine use of adjuvant chemotherapy in clinical practice due to small sample sizes, confusing analyses and terminology, and the reporting of questionable conclusions. Analyses of the duration of survival either were not done or were inconclusive, and quality of life was never considered. Based on the desire to only treat patients who are really at high risk, the EORTC together with many other international groups throughout the world have begun a large adjuvant trial. This study evaluates four cycles of immediate chemotherapy versus therapy at the time of relapse in high-risk patients with pT3-pT4 or node-positive disease. Three different chemotherapy regimens are permitted: M-VAC, high-dose M-VAC (HD-M-VAC), and gemcitabine/cisplatin (GC).
6.4.7 Radiotherapy as primary treatment
There have been no randomized trials comparing RT to surgery in good prognosis T2 and T3 patients. Radical radiotherapy with surgery reserved for salvage of local failure, is considered standard option in the United Kingdom and Canada, and only suitable for individual clinical use in other countries (Fair 1993; Gospodarowicz 1992; Mameghan 1995). In most other European countries, initial cystectomy is more commonly used, with radiation reserved for patients who are medically unfit or who refuse surgery. The largest radiotherapy series, and the only one with long term follow-up, is the Edinburgh series. With a minimum dose of 55 Gy in 4 weeks, 25% 5-year local control was achieved for T1, T2 and T3 patients. In T4 patients, long term local control was 16%. For T2, long-term survival of 40% is generally reported. In selected series, when sophisticated irradiation techniques can be employed, such as a boost of interstitial brachytherapy combined with external beam irradiation, 5-year survival of 56%-60% has been achieved. These modalities of irradiation are considered suitable for individual clinical use. It is of note, however, that in T3 tumors long-term survival falls to 20%. Although the optimum tumouricidal dose level of radiotherapy is unknown, most recent series have recommended a dose of 6500 cGy at daily doses of 180 to 200 cGy to the tumor region, with a restricted dose of 4750 to 5500 cGy dose to the whole bladder and perivesical region. The four field box technique is most often used. This encompasses the whole bladder, the perivesical soft tissues, and the pelvic lymphatics, while minimizing the dose to the rectum and anus. If treatment is delivered with fractions less than 200 cGy, toxicity is reduced. Two different strategies can be adopted: to treat the bladder volume, or to selectively irradiate both the bladder and pelvic nodes, at a dose of about 50 Gy in 5 weeks, with an additional boost to the bladder. No general consensus has been reached on which option should be recommended as standard. Response evaluation is usually based solely upon cystoscopy after RT. With RT alone, some 20-40% of patients are cured and preserve their bladder free of disease (Gospodarowicz 1992; Mameghan 1995). At least 24% of patients have long term morbidity. Toxicities associated with RT include: decreased bladder function, cystitis, hematuria, and adhesions. Prognostic factors for local curability are absence of ureteral obstruction, papillary pattern of growth, and visibly, complete tumor resection by TURB prior to RT. Recurrence in the bladder represents the predominant site of failure after radiotherapy followed by distant metastases. Distant metastases alone represent 10% of all failures. When control of the primary tumor is considered, these data compare unfavorably with most data from surgical series. Taking into consideration the facts that in surgical reports patients are more stringently selected, it is noted that the local relapse rate is definitely lower after surgery than after radiotherapy. Salvage surgery may be offered in patients who relapse. It is important to note that combined data from several large series revealed that only 19% of patients with local persistence or recurrence after full dose radiotherapy underwent cystectomy.
6.5 Metastatic disease (Any T, N+, M+)
6.5.1 Systemic chemotherapy
Systemic cisplatin-containing chemotherapy is considered standard option on a type C basis, for patients with metastatic or advanced TCC, and provides potential for increased survival (Sternberg 1999; Fossa 1996). Antitumour activity has been demonstrated with several single agents, with only rare improvements in survival (Sternberg 1995a). In the past, M-VAC (methotrexate, vinblastine, adriamycin, cisplatin), CMV (cisplatin, methotrexate, vinblastine), CM (cisplatin, methotrexate), and CISCA/CAP (cyclophosphamide, adriamycin, cisplatin), have been considered among the most active regimens for advanced TCC, with survival benefit in patients who attain CR (Sternberg 1999). Randomized trials in advanced disease suggest that cisplatin-containing combination chemotherapy regimens should be considered standard therapy on a type 2 level of evidence. Patients with advanced nodal disease as compared to visceral disease have a higher response rate (71% versus 40%) and survival (33 months versus 12 months). The central nervous system is, however, a sanctuary site. Apart from pulmonary lesions, which respond, visceral lesions, particularly hepatic, are the least responsive. Durable responses are rarely seen in liver or in bone. Response to cisplatin-based therapy usually occurs rapidly. Elderly patients > 70 years old, particularly those with compromised performance status, may be treated by reducing all doses of chemotherapy by 20-30%, in order to evaluate their tolerance to therapy, or by substituting cisplatin with carboplatin, although this is probably less effective.
6.5.2 New strategies, drugs, and combinations
The use of combination chemotherapy results in long-term survival in approximately 15-20 % of patients. Effective salvage strategies are needed. Phase II trials have traditionally been performed in patients with exposure to at least one prior combination regimen. Only a few drugs have demonstrated response above 15 %. New agents must be tested in patients who have less extensive disease and a good performance status. Patients with a partial response after first-line chemotherapy or who have selected visceral disease may be appropriate candidates for investigational therapy. Approaches to the management of advanced bladder carcinoma include: intensifying the dose intensity, doublet and triplet combination chemotherapy, sequential regimens, reducing toxicity in unfit or elderly patients, and the use of biologic targeted therapies and promising new chemotherapeutic agents. These include MTA, the epothilones, topoisomerase inhibitors and vinflunine which act upon folate metabolism or upon different phases of the cell cycle. New agents that are coming into clinical trials include farnesyl transferase inhibitors, several growth factors receptor inhibitors, and Cox-2 inhibitors. These strategies are investigational (Sternberg 2003b).
6.5.2a Hematopoietic growth factors and dose intensity
Strategies to increase CR include augmenting the dose of chemotherapy with hematologic growth factor support. After initial favorable reports of responses in heavily pre-treated patients with escalated M-VAC and growth factors, several groups began phase II trials of escalated chemotherapy, but later abandoned this approach due to excessive toxicity. The EORTC Genitourinary Group trial has addressed the issue of dose-intensity in a randomized trial compared to standard M-VAC. High dose M-VAC (HD-M-VAC) given every 2 weeks with G-CSF was compared to classic M-VAC. It was possible to deliver twice the dose of cisplatin and doxorubicin with less toxicity, fewer dose delays, and in half of the time, if G-CSF was routinely added. This trial revealed less toxicity with HD-M-VAC due to the addition of G-CSF. Although there was not a significant difference found in median survival (> 14 months in both arms), there was a significant difference in favor of HD-M-VAC in response rate (RR), and CR rate. Of note, 2-year survival was 35% with HD-M-VAC compared to 25% with M-VAC. Escalated dosage M-VAC can not be recommended as standard therapy at this time on a type 1 level of evidence, but this treatment modality is interesting on an individualized basis if chemotherapy is given in the neo-adjuvant, so that surgery is not unduly delayed.
Gemcitabine is an antimetabolite that inhibits DNA synthesis, and is an analogue of cytosine arabinoside. Gemcitabine is usually given weekly for 3 weeks, every 4 weeks. As a single agent response rates of 25 % to 29 % have been obtained both in pre-treated patients and in those who have not had a prior therapy (Pollera 1994; Lorusso 1998; Moore 1997; Stadler 1997). Phase II pilot studies, have combined Gemcitabine with cisplatin (von der Maase 1997) A 40% response rate was obtained, with a median survival of 12.1 months. Significant myelosuppression, particularly thrombocytopenia resulted, most likely due to the unusual dosage schedule of cisplatin chemotherapy. However, responses were seen both in osseous and hepatic sites. The dosage and schedule of cisplatin have been modified to an every 4 week dosage in a randomized international trial comparing gemcitabine on days 1, 8 and 15 and cisplatin at 70 mg/m² every 4 weeks to M-VAC without G-CSF (von der Maase 2000). This study showed a similar survival advantage but the combination of Cisplatin and Gemcitabine (GC) was better tolerated. For this reason, many investigators have adapted the GC combination as another standard of chemotherapy on a type 2 level of evidence.
6.5.2c The Taxanes
Paclitaxel (Taxol) and docetaxel (Taxotere) share a similar mechanism of action: the promotion of microtubule assembly and inhibition of microtubule disassembly. Taxol is the active ingredient of the bark. Taxotere was prepared from the needles of Taxus baccata. A 42 % response rate (27 % CR) was reported in previously untreated patients when a relatively high dose of Taxol (250 mcg/ m²) was administered with G-CSF (Roth 1994). Other investigators have combined Taxol with cisplatin or carboplatin, plus growth factors in untreated patients, and have revealed high response rates of 50-80 %, not necessarily correlated with improved survival on a type 3 level of evidence (Sternberg 1999). Docetaxel, another widely used taxane also has displayed activity in TCC. In previously treated patients the RR was 13% with a median overall survival of 9 months (McCaffrey 1997). In untreated patients, the RR was higher; 38% with a median duration of response of 6 months (de Wit 1998). The combination of docetaxel and cisplatin every 3 weeks has been evaluated in 3 studies (Sengelov 1998; Dimopoulos 1999; Garcia del Muro 2002). In more than 120 patients, the overall RR was 52% – 62% and the median overall survival ranged from 8.2 to 13.6 months. Although phase II studies of 2 drug combinations of paclitaxel or docetaxel with cisplatin, have shown activity in untreated patients, with response rates that are similar to M-VAC, they have not been directly compared to M-VAC in a phase III trial.
6.5.2d Doublet and triplet regimens
The combination of gemcitabine and a taxane is active and well tolerated as first- or second-line treatment of patients with advanced TCC, as well as in patients with compromised renal function. Response rate and duration compare favorably with those produced by other active, first-line regimens (Stadler 2002; Sternberg 2001d). Other combinations using the taxanes and gemcitabine have been put forth as possible alternatives to M-VAC. Both gemcitabine and paclitaxel have been incorporated into multi-agent chemotherapy combinations with cisplatin or carboplatin (Hussain 2002). Phase II data from two gemcitabine-based triplets are currently available. The Spanish regimen of gemcitabine, paclitaxel and cisplatin (GCP) has led to a very high RR of around 78% (CR 28% and PR 50%) (Bellmunt 2000). The first report from the phase I trial reported survival of 24 months, probably due to patient selection. In the multi-center phase II study, the median survival was 15.6 months, more consistent with other currently available regimens (Bellmunt 2000). The American combination study of gemcitabine, paclitaxel and carboplatin (rather than cisplatin) compared favorably to the Spanish regimen with a 14.7 month median survival, and 1-year survival of 59%. The RR was 68% (CR 32% and PR 36%) (Hussain 2001). In another study from MSKCC, the triplet ifosfomide, paclitaxel and cisplatin (ITP) revealed a 68% RR (CR 23% and 45% PR). Median survival was 20 months in this single center study (Bajorin 2000). Whether or not we are really improving upon survival with these new regimens will depend upon the results of ongoing phase III trials.
6.5.3 Palliative radiotherapy
Advanced carcinoma of the bladder with pelvic fixation carries a poor prognosis and no significant differences in results can be shown whether the patient is treated with a radical intent or a palliative one. Palliation of symptoms remains the principal aim, taking care to avoid severe reactions. Patients should be carefully selected, as those in very poor conditions or with grossly reduced bladder capacity can have their symptoms aggravated by radiation. Hematuria may be controlled by a short course of irradiation in about 50% of cases. Pelvic pain can be due to a bladder mass or to bone lesions, with or without nerve involvement. If the site of illness is well identified, pain control may be achieved in over 50% of cases. Palliation is generally obtained with doses of about 30 Gy in two weeks; shorter regimens are generally excluded in order to avoid toxicity. Single fraction treatments with 8 or 10 Gy to a well circumscribed bladder volume are reported as safe and effective in controlling hematuria. Painful bone metastasis in other sites than pelvis can be treated effectively with the radiotherapy modalities generally adopted for skeletal metastases.
6.5.4 New target oriented drugs
With the introduction of combination chemotherapy regimens including cisplatin and methotrexate for the management of metastatic urothelial cancer, median overall survival has doubled. Nevertheless, death due to cancer ultimately occurs in more than 80% of these patients, thus more effective therapy is required. The new available treatment modalities range from new combinations of conventional chemotherapeutic agents to combinations incorporating novel drugs like gemcitabine and the taxanes. These new combinations incorporate the new active agents in two, three or multiple drug combinations, administered either in one regimen or sequentially in various combinations and schedules intended to improve the outcome of bladder cancer patients. Ongoing phase III studies will help to define the role of these new combinations in the treatment of advanced bladder cancer. The improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new prognostic indices that can direct the most appropriate choice of treatment for advanced disease. In addition, advances in the molecular biology of urothelial malignancies may allow identification of specific genetic lesions and biochemical pathways upon which future therapeutic approaches can be focused. The integration of newer biologic agents, probably to supplement rather than to supplant chemotherapeutic drugs, should be a primary direction of research with the objective to interfere with multiple aspects of bladder cancer progression. Integration of trastuzumab in the treatment of urothelial carcinoma has been investigated in a phase II multicenter trial. HER2 is overexpressed in >50% of metastatic urothelial cancer. Patients eligible for therapy (HER2 overexpressed and/or gene amplification by FISH) have been treated with a combination chemotherapy (paclitaxel, carboplatin, gemcitabine) in addition to trastuzumab. The combination is feasible and is associated with high level of activity (Hussain 2005).
7. LATE SEQUELAE
7.1 Late sequelae related to surgery
Complications of TURB are rare, and may consist of hemorrhage, hypotonic overhydration due to fluid absorption, urinary retention, urethral stenosis, and incontinence. The risk of complications may depend upon the volume and surface area resected, and upon the surgical skill of the urologist. Intentional perforation of the bladder should not be viewed as a complication since a whole thickness specimen of the bladder wall is requested in order to appropriately stage the disease. Minor bladder perforations repair spontaneously in most cases, if the vesical catheter is maintained for 48 hours post operatively. Although radical cystectomy represents a major surgical procedure, the mortality rate is relatively low, (1 to 2 %) (Soloway 1994; Amling 1994; Freiha 1992). Major complications may occur in up to 25 to 35% of patients and include: wound infections, intestinal obstruction, haemorrhage, and cardiopulmonary complications. Rectal injury may occur during cystectomy, with a reported incidence of around 4%. If the rectal injury is small and fecal contamination is minimal, in a non- irradiated patient, it may be closed primarily and a diverting colostomy is only rarely required. The re-operation rate following radical cystectomy is around 10 percent. The re-operation rate increases after urinary reconstruction and is proportional to the complexity of the reservoir constructed.
7.2 Late effects and sequelae related to radiotherapy
With RT at least 24% of patients have long term morbidity (Rotman 1987). Toxicities associated with RT include: decreased bladder function, cystitis, hematuria, and adhesions. However, with optimal technique and dosage, irradiation caused morbidity can be reduced. Several factors predispose to severe acute reactions, and eventually late sequelae:
1. previous repeated surgical procedures;
2. obstructive uropathy;
3. bladder infection;
4. large ulcerative or necrotic tumor.
One year or more after irradiation, most patients have mild to moderate telangiectasis, sometimes associated with limited bleeding. When necessary, cauterization will stop the bleeding. Severe hemorrhagic cystitis is an uncommon late complication, and in extremely rare cases cystectomy needs to be performed. A contracted bladder may result if the walls of the bladder become fibrotic after irradiation; in severe cases, the bladder capacity is reduced to only 50 ml. This complication occurs in 4% of the cases, particularly if repeated TURB have preceded irradiation. Fistulas (vesicovaginal, vesicorectal, or ureteral) can occur early after radiotherapy; in such cases it is usually a manifestation of the advanced disease in which tumor regression has left a fistula. If a fistula occurs more than 1 year after treatment, it is usually due to improper treatment or high dosage of therapy. Repeated TURB may also predispose to fistula formation. Small bowel obstruction and necrosis may in patients after cystectomy followed by radiation, if loops of small bowel are trapped in the pelvis due to adhesions.
8. FOLLOW UP
8.1 General Strategy
A follow-up schedule should detect recurrent tumours and tumours at risk of progression early enough to be cured and should not be an economic burden and emotional stress to the patient.
8.1.1 Follow-up after conservative management (superficial tumours)
The follow-up schedule is dependent on the natural history of the disease (i.e. the expected progression rate) (Parmar 1989). Patients with Ta, T1, G1, G2, tumors should be followed 3 to 4 times a year during the first year and at six months intervals thereafter. Patients with G3 T1 tumors (or Cis) should be followed at 3 month intervals during the first 3 years and at six months intervals thereafter. The follow-up schedule should include cytology and cystoscopy. Urine cytology is most helpful in patients with high grade lesions and of less help in low grade lesions. The fluorescence in situ hybridisation test, F.I.S.H., named Uro Vysion (Vysis-Abbott, Downers Grove, IL) stains four chromosomes, namely, 3, 7, 17, and the 9p21 gene locus and has been reported to increase the detection of the cancer cells over standard cytology (Sokolova 2000; Bubendorf 2001) It represents a powerful aid ancillary to cystoscopy in the follow-up of recurrences. Other tests to aid in the diagnosis along with cystoscopy, or possibly to replace cystoscopy (i.e. BTA test), are considered investigational.
8.1.2 Follow up after radical surgery
Recurrences in the urethra and the upper urinary tract, which can occur after radical cystectomy, can be cured if detected at an early stage. Patients can also develop local recurrences in the pelvis or metastases at distant sites. The rationale of follow-up, therefore, is to monitor the urethra, upper tract, the pelvis, and the most common sites of metastases. Urethral recurrences are reported in 3.5 to 17% of cases (Tongaonkar 1993). The incidence of upper urinary tract recurrences following cystectomy ranges from 1 to 9% (Braslis 1994). In order to detect upper tract disease, a yearly IVP or CT scan is performed. Distant metastases can occur in the liver, the lungs, and in the skeleton and are discovered by CT scans, chest films or CT scans, and bone scans that should be performed on a yearly basis.
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Dr. Giuseppe Curigliano (Author)
European Institute of Oncology – Milan, Italy
Dr. Filippo de Braud (Editor)
START Clinical Editor – European Institute of Oncology – Milan, Italy
Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
Dr. Massimo Maffezzini (Author)
Ospedali Galliera – Genoa, Italy
Prof. Cora N. Sternberg (Reviewer)
Fondazione Vincenzo Pansadoro – Rome, Italy
Prof. Cora N. Sternberg (Author)
Fondazione Vincenzo Pansadoro – Rome, Italy
Dr. Vito Vitale (Author)
Istituto Nazionale per la Ricerca sul Cancro – Genoa, Italy
Dr. Maria Teresa Giannelli
Redazione START Fondazione IRCCS ‘quot;Istituto Nazionale dei Tumori’quot; – Milan, Italy
Dr.ssa Chiara Rossini