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Bladder Cancer
UROLOGY
cytological features. These tumours are usually confined to the urothelium and lamina propria (the remainder take the form of a solid tumour: these are usually poorly differentiated and invading the underlying detrusor muscle). Tumours are frequently multifocal. TCCs are graded cytologically using the WHO system of grades I–III with increasing differentiation. Most tumours arise initially on the posterior and lateral walls of the bladder. Whilst dysplasia surrounding a tumour is relatively common, a small number of patients have only carcinoma in situ, Tis, and no invasive carcinoma. The appearance of this varies from urothelium that appears normal through to reddened areas suggestive of an inflammatory or infective origin. Whilst Tis does not breach the basement membrane, the cells are cytologically equivalent to those in a GIII tumour, and are associated with the subsequent development of carcinoma which invades muscle in approximately 50% of cases. SCCs arise from areas of urothelium that have undergone squamous metaplasia. Adenocarcinoma of the bladder is uncommon. It may arise from nests of glandular tissue in the urachal remnant or following glandular metaplasia. Intestinal metaplasia of the urothelium, although a rare finding, is a premalignant phase of adenocarcinoma. Leiomyomas and sarcomas of detrusor occur rarely. Local invasion, from advanced pelvic neoplasms, is well recognized. Distant metastases from other tumours are a very infrequent mode of presentation, although this has been described for primary breast and lung cancers.
Bladder Cancer J Phillips V Kumar Gordon Bryden
It is with great sadness that I write to dedicate this paper to the memory of Gordon Bryden. Unfortunately Gordon died in tragic circumstances following an accident. This excellent article is attributed to his clear thinking. All of us at Sheffield are saddened by the loss of a fantastic colleague, a fine academic and a superb clinician who, without doubt, would have made a significant contribution to the field of uro-oncology. Chris Chapple FRCS(Urol) FEBU Consultant Urological Surgeon, Royal Hallamshire Hospital, Honorary Senior Lecturer, Sheffield University, UK, and Specialty Editor, Surgery journal.
Bladder cancer constitutes a significant proportion of the general urological workload due to its high prevalence and recurrent nature. This contribution outlines the key points in the diagnosis, staging and management of urothelial tumours of the urinary bladder.
Aetiology There are a number of aetiological factors associated with bladder cancer and they are discussed below:
Incidence Bladder cancer is the fourth most common malignancy in England and Wales, affecting 1 in 4000 people and accounting for around 5% of all diagnosed cancers. The peak incidence is between the fifth and seventh decades and there is a 2:1 male-to-female ratio. Despite an increasing incidence over the last half-century, mortality rates from bladder cancer declined by 8% between 1980 and 1995.
Cigarette smoking: around 50% of all TCCs are associated with cigarette smoking. There is an overall four-fold increase in risk, but this is correlated directly with duration of smoking and number of cigarettes smoked. Cessation of smoking, even after many years, can be beneficial, as ex-smokers have a reduced incidence of bladder cancer compared with ‘current’ smokers. Chemical (occupational) carcinogens: the association between exposure to benzidine, aromatic amines and β-naphthylamine, typically in the dye and rubber industries, is associated with a thirty-fold increased risk of TCC. A history of occupational carcinogen exposure may entitle a patient to compensation. Other industries such as textiles, leather works, printing, aluminium refining, hairdressing and rodent control have been linked less strongly with the development of bladder cancer. Other carcinogen exposure may occur through coarse fishing, where maggots used as bait may be dyed with chrysoidin. Chemical exposure and smoking may be synergistic. The latent period between carcinogen exposure and tumour development may be prolonged.
Pathology In the UK, around 95% of all bladder tumours are transitional cell carcinomas (TCCs) of the urothelium. Adenocarcinoma and squamous cell carcinoma (SCC) account for around 2% each. The majority of TCCs are papillary in nature, exhibiting fronds covered by an abnormally thick layer of urothelium with atypical
J Phillips is a Research Fellow in Urology at the Royal Hallamshire Hospital, UK. He carried out his basic surgical training in Sheffield, UK. V Kumar is a Specialist Registrar in Urology at the Royal Hallamshire Hospital, UK. He carried out his basic surgical training at Delhi University, India.
Schistosomiasis: bilharziasis is associated with the development of bladder SCCs, and remains the most common cause of bladder cancer worldwide. In endemic areas of bilharzia, 75–90% of all tumours are SCCs, often occuring at a younger age and are usually advanced at presentation with a poor prognosis.
Gordon Bryden was Senior Lecturer in Urology at the Royal Hallamshire Hospital Sheffield Teaching Hospitals NHS Trust, UK.
SURGERY
281
© 2002 The Medicine Publishing Company Ltd
UROLOGY
Chronic inflammation: inflammatory stimuli such as chronic infection, long-term in-dwelling catheters or bladder stones can be associated with squamous metaplasia and an increased incidence of bladder cancer.
is therefore mandatory to visualize the upper urinary tract, usually by intravenous urography (IVU) or occasionally retrograde pyelography, as there may be a synchronous tumour in the ureter or renal pelvis. IVU will also give some information regarding renal function and ureteric obstruction. Urine cytology has a limited, but useful, role in diagnosis. In grade I tumours, cytology is positive in only approximately 25% of cases. However, with poorly differentiated disease or cis, this rises to 75–80%. In cases with positive cytology, it is prudent to take systematic biopsies of the urothelium to identify either cis remote from a tumour or primary carcinoma in situ. Persistently positive cytology in the absence of abnormalities on cystoscopy, quadrant bladder biopsy and with normal upper tracts on IVU, should prompt a further cystoscopy in case a tumour has been overlooked, with ureterorenoscopy to identify a small upper tract tumour.
Pelvic irradiation: bladder cancer may occur as a second malignancy in those previously treated by radical radiotherapy for pelvic cancers. Clinical features Frank, painless haematuria is the cardinal symptom of bladder cancer. Haematuria, whether frank or microscopic, warrants investigation to exclude bladder cancer, particularly in those aged >40 years. In around 15% of cases, patients present with irritative lower urinary tract symptoms (frequency, dysuria, urgency) suggestive of infection or urolithiasis, with or without haematuria. Suspicion should be aroused if the urine is sterile and symptoms respond poorly to antibiotics. In particular, carcinoma in situ may present in this way. A small number of patients present with uraemia due to bilateral ureteric obstruction or the symptoms of metastatic disease.
Staging The tumour/nodes/metastases (TNM) system is universally used for bladder cancer, based on the depth of invasion through the bladder wall (Figure 2) in combination with the presence or absence of metastatic pelvic lymph node involvement and distant metastases. Carcinoma in situ is represented as Tis. Stages Ta and T1 are described as superficial bladder cancers, where the tumour is limited to the mucosa or penetrates into the lamina propria respectively. Stage T2 and above have invasion of the detrusor muscle, with full-thickness penetration in T3, and invasion of adjacent structures in T4 (Figure 2). Histological analysis of the resection specimens gives a
Diagnosis Cystoscopy permits diagnostic confirmation of bladder cancer (Figure 1) where, under anaesthetic, a tumour may be resected or representative biopsies obtained. TCC is a pan-urothelial disease and may be multifocal. It
a
c
b
Superficial endoscopic views of bladder tumours. a in a diverticulum b at the bladder base on the trigone c a pedunculated lesion d a lesion in the prostatic urethra
d
1 SURGERY
282
© 2002 The Medicine Publishing Company Ltd
UROLOGY
����������������������
Peritoneum Subserosa and perivesical fat
��������������� Tis (0)+
Epithelium Lamina propria Muscle
Deep muscle
Ta(0)
Muscle Deep longitudinal layers Middle circular and inner longitudinal layers Submucosa (Lamina propria)
T1(A)
Mucosa (Epithelium)
T2a(B1) T2b(B2)
T3(C) Perivescal fat (or peritoneum)
T4(D1) T3a – microscopic invasion perivesical tissue T3b – macroscopic invasion perivesical tissue T4a – invasion of prostate, uterus, vagina T4b – invasion of pelvic or abdominal wall
Prostate (contiguous organs)
2
pathological staging (pT stage). This will differentiate Ta and T1 tumours from those invading muscle. However, T2–4 will all be reported as pT2 as local extent beyond detrusor cannot be assessed in resection chips alone. Muscle-invasive tumours are staged clinically by a combination of bimanual examination under anaesthetic (at the time of cystoscopy/resection) and cross-sectional imaging. Magnetic resonance imaging (MRI) scanning is the modality of choice for assessment of local tumour invasion and pelvic lymph node status. Tumours that invade the detrusor muscle are generally high grade and highly malignant, with a strong potential to metastasize. Before contemplating radical treatment of an invasive tumour, it is routine to exclude distant metastases by liver ultrasound and chest radiograph. If there are suggestive signs or symptoms, an isotope scan is performed to identify bone metastases.
following resection has been shown to reduce recurrence rates. Large or multifocal tumours are associated with a higher recurrence rate than small, solitary ones. In these situations, transurethral resection may be followed by a course of 6–10 instillations of a chemotherapeutic agent (e.g. mitomycin C, epirubicin or thiotepa) at weekly intervals. Endoscopic surveillance is performed by flexible cystoscopy at three-month intervals for the first year, six-month intervals for the second, and annually thereafter. The risk of progression in superficial bladder cancer depends predominantly on tumour grade, and rates range from 2% for pTaGI tumours through to 30% for pT1GII. Carcinoma in situ or pTa/1GIII tumours are much more worrying, they are associated with the development of muscle-invasive disease in >50% of cases by 2 years. For such high-grade disease or T1 tumours, intravesical immunotherapy with live attenuated Bacille Calmette–Guerin (BCG) is more effective. BCG instillation into the bladder stimulates a non-specific immune response with a proven reduction in tumour recurrence and prolongation in time to muscle invasion or metastasis. This is given as a course of 6 instillations on a weekly basis, and a small number of centres may continue with ‘maintenance therapy’ at 3–6-month intervals. The presence of Tis/high-grade disease or multifocal tumours refractory to immunotherapy or chemotherapy respectively is an indication for radical surgery. The overall 5-year survival rate for patients with superficial bladder cancer is currently around 95%.
Treatment of superficial tumours Over three-quarters of bladder cancers are superficial (Ta/T1) at time of presentation. It is usually possible to remove all visible tumour by endoscopic resection. However, following transurethral resection alone, 50–70% of patients with Ta/T1 tumours will have recurrence within 2 years. This is due either to instability of the urothelium or implantation of malignant cells into traumatized urothelium at the time of resection. To reduce this, many patients are treated adjuvantly with intravesical agents. These liquid agents are instilled into the bladder, kept in the bladder for 1–2 hours, and then voided. A single dose of intravesical chemotherapy (mitomycin C) immediately
SURGERY
283
© 2002 The Medicine Publishing Company Ltd
UROLOGY
Treatment of muscle-invasive tumours Approximately 20% of new cases already have tumour invasion into the detrusor muscle at diagnosis. Invasive bladder cancer has a 3-year survival of less than 5% in untreated cases. Furthermore, these tumours cannot be eradicated by transurethral resection alone or by intravesical therapy. Definitive treatment is either by radical surgery (cystectomy) or radical external beam radiotherapy. In these cases transurethral resection provides diagnostic and grading/staging information only.
on disease stage. The 5-year survival rates are 85% for T2 cancers, 55% for T3 and less than 25% for those with stage T4. SCC and adenocarcinoma Both these tumours are radio-resistant. The primary treatment of SCC is radical surgery but, despite this, the prognosis is poor and, even with the addition of adjuvant radiotherapy and chemotherapy, the 5-year survival remains at only 45–50%. Adenocarcinoma is treated by open excision, either partial cystectomy if the tumour location allows, or by radical cystectomy and urinary diversion/reconstruction.
Radical radiotherapy: following appropriate staging and planning investigations, invasive bladder cancers can be treated with a course of radiotherapy (64 Gy in 32 fractions). Radiotherapy has the advantage of bladder preservation, but may be associated with frequency and urgency along with future bladder contracture. It is relatively contraindicated in those patients with small bladder capacity (<300 ml) or pre-existing irritative lower urinary tract symptoms. Fifty percent of patients will exhibit a complete response to radiotherapy. Following irradiation, endoscopic surveillance is resumed. In the event of recurrent or refractory tumour, salvage cystectomy may be contemplated. This is technically more difficult than primary cystectomy due to radiation fibrosis, and generally precludes bladder reconstruction.
Metastatic bladder cancer Metastatic bladder cancer has a dismal prognosis, the mean survival being 6–12 months. Treatment is targeted primarily at symptom palliation. This may involve local tumour resection or palliative radiotherapy to control haematuria. Symptoms from metastases can be palliated with irradiation to bone or soft tissue. Involvement of palliative care services is frequently useful. Unfortunately, metastatic TCC is relatively chemo-resistant. Combination therapy with methotrexate, vinblastin, adriamycin and cisplatin (M-VAC) has shown a complete response in up to 20% of patients. However, this is a toxic combination (in one series the mortality of treatment was 4%) and long-term survivors are few. Future perspectives Bladder cancer is a common disease and treatment is determined primarily by whether the tumour is superficial or invasive. Therapy for the former is primarily endoscopic with or without intravesical agents. Muscle-invasive disease requires radical therapy. It is important to be familiar with the recurrent nature of superficial bladder cancer and to identify the factors that may predict progression to muscle invasion. u
Radical cystectomy: primary radical cystectomy has become the treatment of choice in bladder cancer invading the muscle. Preoperative assessment of general fitness and cardiorespiratory status is an important consideration before such major pelvic surgery. In males, a cystoprostatectomy +/- urethrectomy: the en bloc removal of the bladder, prostate, seminal vesicles, perivesical fat and pelvic peritoneum is performed. In females, an anterior pelvic clearance (en bloc removal of the bladder, anterior vaginal wall (including urethra), ovaries, uterus and pelvic peritoneum) is carried out. As part of radical surgery for bladder cancer it is routine to perform a pelvic node dissection. This is generally done to provide prognostic information, although there is emerging data to suggest a survival advantage in the presence of micrometastatic disease. Historically, the standard reconstruction after total cystectomy has been to form an incontinent urostomy where a conduit of ileum is anastomosed to the ends of the ureters and brought out as a stoma in the right iliac fossa. However, if the primary tumour is away from the bladder neck, the patient may be offered an orthotopic bladder reconstruction as an alternative to a urostomy. In this procedure, a neobladder is fashioned from a length of detubularized small or large bowel mobilized on its pedicle, which is then transformed into a cylindrical or spherical shape, with a resultant 33–50% increase in volume. The ureters are implanted into this and the apex anastomosed to the urethra. This avoids a stoma with the consequent benefits for body image and, with motivation and education, the patient is able to achieve continence. In the event of a urethrectomy being necessary, a final option is that of a continent urinary diversion, where a similar reservoir is formed from bowel, but connected to skin level by a catheterizable stoma incorporating a valvular mechanism. The prognosis in muscle-invasive bladder cancer is dependent
SURGERY
FURTHER READING Cohen S M, Johansson S L. Epidemiology and etiology of bladder cancer. Urol Clin North Am 1992; 19(3): 421–8. Enstoff M S, Heaney J A, Peschel R F. Urological Cancer. Oxford: Blackwell Science, 1997. Kamat A M, Lamm D L. Intravesical therapy for bladder cancer. Urology 2000; 55(2): 161–8. van der Meijden A P. Bladder cancer. BMJ 1998; 317(7169): 1366–9.
284
© 2002 The Medicine Publishing Company Ltd
cytological features. These tumours are usually confined to the urothelium and lamina propria (the remainder take the form of a solid tumour: these are usually poorly differentiated and invading the underlying detrusor muscle). Tumours are frequently multifocal. TCCs are graded cytologically using the WHO system of grades I–III with increasing differentiation. Most tumours arise initially on the posterior and lateral walls of the bladder. Whilst dysplasia surrounding a tumour is relatively common, a small number of patients have only carcinoma in situ, Tis, and no invasive carcinoma. The appearance of this varies from urothelium that appears normal through to reddened areas suggestive of an inflammatory or infective origin. Whilst Tis does not breach the basement membrane, the cells are cytologically equivalent to those in a GIII tumour, and are associated with the subsequent development of carcinoma which invades muscle in approximately 50% of cases. SCCs arise from areas of urothelium that have undergone squamous metaplasia. Adenocarcinoma of the bladder is uncommon. It may arise from nests of glandular tissue in the urachal remnant or following glandular metaplasia. Intestinal metaplasia of the urothelium, although a rare finding, is a premalignant phase of adenocarcinoma. Leiomyomas and sarcomas of detrusor occur rarely. Local invasion, from advanced pelvic neoplasms, is well recognized. Distant metastases from other tumours are a very infrequent mode of presentation, although this has been described for primary breast and lung cancers.
Bladder Cancer J Phillips V Kumar Gordon Bryden
It is with great sadness that I write to dedicate this paper to the memory of Gordon Bryden. Unfortunately Gordon died in tragic circumstances following an accident. This excellent article is attributed to his clear thinking. All of us at Sheffield are saddened by the loss of a fantastic colleague, a fine academic and a superb clinician who, without doubt, would have made a significant contribution to the field of uro-oncology. Chris Chapple FRCS(Urol) FEBU Consultant Urological Surgeon, Royal Hallamshire Hospital, Honorary Senior Lecturer, Sheffield University, UK, and Specialty Editor, Surgery journal.
Bladder cancer constitutes a significant proportion of the general urological workload due to its high prevalence and recurrent nature. This contribution outlines the key points in the diagnosis, staging and management of urothelial tumours of the urinary bladder.
Aetiology There are a number of aetiological factors associated with bladder cancer and they are discussed below:
Incidence Bladder cancer is the fourth most common malignancy in England and Wales, affecting 1 in 4000 people and accounting for around 5% of all diagnosed cancers. The peak incidence is between the fifth and seventh decades and there is a 2:1 male-to-female ratio. Despite an increasing incidence over the last half-century, mortality rates from bladder cancer declined by 8% between 1980 and 1995.
Cigarette smoking: around 50% of all TCCs are associated with cigarette smoking. There is an overall four-fold increase in risk, but this is correlated directly with duration of smoking and number of cigarettes smoked. Cessation of smoking, even after many years, can be beneficial, as ex-smokers have a reduced incidence of bladder cancer compared with ‘current’ smokers. Chemical (occupational) carcinogens: the association between exposure to benzidine, aromatic amines and β-naphthylamine, typically in the dye and rubber industries, is associated with a thirty-fold increased risk of TCC. A history of occupational carcinogen exposure may entitle a patient to compensation. Other industries such as textiles, leather works, printing, aluminium refining, hairdressing and rodent control have been linked less strongly with the development of bladder cancer. Other carcinogen exposure may occur through coarse fishing, where maggots used as bait may be dyed with chrysoidin. Chemical exposure and smoking may be synergistic. The latent period between carcinogen exposure and tumour development may be prolonged.
Pathology In the UK, around 95% of all bladder tumours are transitional cell carcinomas (TCCs) of the urothelium. Adenocarcinoma and squamous cell carcinoma (SCC) account for around 2% each. The majority of TCCs are papillary in nature, exhibiting fronds covered by an abnormally thick layer of urothelium with atypical
J Phillips is a Research Fellow in Urology at the Royal Hallamshire Hospital, UK. He carried out his basic surgical training in Sheffield, UK. V Kumar is a Specialist Registrar in Urology at the Royal Hallamshire Hospital, UK. He carried out his basic surgical training at Delhi University, India.
Schistosomiasis: bilharziasis is associated with the development of bladder SCCs, and remains the most common cause of bladder cancer worldwide. In endemic areas of bilharzia, 75–90% of all tumours are SCCs, often occuring at a younger age and are usually advanced at presentation with a poor prognosis.
Gordon Bryden was Senior Lecturer in Urology at the Royal Hallamshire Hospital Sheffield Teaching Hospitals NHS Trust, UK.
SURGERY
281
© 2002 The Medicine Publishing Company Ltd
UROLOGY
Chronic inflammation: inflammatory stimuli such as chronic infection, long-term in-dwelling catheters or bladder stones can be associated with squamous metaplasia and an increased incidence of bladder cancer.
is therefore mandatory to visualize the upper urinary tract, usually by intravenous urography (IVU) or occasionally retrograde pyelography, as there may be a synchronous tumour in the ureter or renal pelvis. IVU will also give some information regarding renal function and ureteric obstruction. Urine cytology has a limited, but useful, role in diagnosis. In grade I tumours, cytology is positive in only approximately 25% of cases. However, with poorly differentiated disease or cis, this rises to 75–80%. In cases with positive cytology, it is prudent to take systematic biopsies of the urothelium to identify either cis remote from a tumour or primary carcinoma in situ. Persistently positive cytology in the absence of abnormalities on cystoscopy, quadrant bladder biopsy and with normal upper tracts on IVU, should prompt a further cystoscopy in case a tumour has been overlooked, with ureterorenoscopy to identify a small upper tract tumour.
Pelvic irradiation: bladder cancer may occur as a second malignancy in those previously treated by radical radiotherapy for pelvic cancers. Clinical features Frank, painless haematuria is the cardinal symptom of bladder cancer. Haematuria, whether frank or microscopic, warrants investigation to exclude bladder cancer, particularly in those aged >40 years. In around 15% of cases, patients present with irritative lower urinary tract symptoms (frequency, dysuria, urgency) suggestive of infection or urolithiasis, with or without haematuria. Suspicion should be aroused if the urine is sterile and symptoms respond poorly to antibiotics. In particular, carcinoma in situ may present in this way. A small number of patients present with uraemia due to bilateral ureteric obstruction or the symptoms of metastatic disease.
Staging The tumour/nodes/metastases (TNM) system is universally used for bladder cancer, based on the depth of invasion through the bladder wall (Figure 2) in combination with the presence or absence of metastatic pelvic lymph node involvement and distant metastases. Carcinoma in situ is represented as Tis. Stages Ta and T1 are described as superficial bladder cancers, where the tumour is limited to the mucosa or penetrates into the lamina propria respectively. Stage T2 and above have invasion of the detrusor muscle, with full-thickness penetration in T3, and invasion of adjacent structures in T4 (Figure 2). Histological analysis of the resection specimens gives a
Diagnosis Cystoscopy permits diagnostic confirmation of bladder cancer (Figure 1) where, under anaesthetic, a tumour may be resected or representative biopsies obtained. TCC is a pan-urothelial disease and may be multifocal. It
a
c
b
Superficial endoscopic views of bladder tumours. a in a diverticulum b at the bladder base on the trigone c a pedunculated lesion d a lesion in the prostatic urethra
d
1 SURGERY
282
© 2002 The Medicine Publishing Company Ltd
UROLOGY
����������������������
Peritoneum Subserosa and perivesical fat
��������������� Tis (0)+
Epithelium Lamina propria Muscle
Deep muscle
Ta(0)
Muscle Deep longitudinal layers Middle circular and inner longitudinal layers Submucosa (Lamina propria)
T1(A)
Mucosa (Epithelium)
T2a(B1) T2b(B2)
T3(C) Perivescal fat (or peritoneum)
T4(D1) T3a – microscopic invasion perivesical tissue T3b – macroscopic invasion perivesical tissue T4a – invasion of prostate, uterus, vagina T4b – invasion of pelvic or abdominal wall
Prostate (contiguous organs)
2
pathological staging (pT stage). This will differentiate Ta and T1 tumours from those invading muscle. However, T2–4 will all be reported as pT2 as local extent beyond detrusor cannot be assessed in resection chips alone. Muscle-invasive tumours are staged clinically by a combination of bimanual examination under anaesthetic (at the time of cystoscopy/resection) and cross-sectional imaging. Magnetic resonance imaging (MRI) scanning is the modality of choice for assessment of local tumour invasion and pelvic lymph node status. Tumours that invade the detrusor muscle are generally high grade and highly malignant, with a strong potential to metastasize. Before contemplating radical treatment of an invasive tumour, it is routine to exclude distant metastases by liver ultrasound and chest radiograph. If there are suggestive signs or symptoms, an isotope scan is performed to identify bone metastases.
following resection has been shown to reduce recurrence rates. Large or multifocal tumours are associated with a higher recurrence rate than small, solitary ones. In these situations, transurethral resection may be followed by a course of 6–10 instillations of a chemotherapeutic agent (e.g. mitomycin C, epirubicin or thiotepa) at weekly intervals. Endoscopic surveillance is performed by flexible cystoscopy at three-month intervals for the first year, six-month intervals for the second, and annually thereafter. The risk of progression in superficial bladder cancer depends predominantly on tumour grade, and rates range from 2% for pTaGI tumours through to 30% for pT1GII. Carcinoma in situ or pTa/1GIII tumours are much more worrying, they are associated with the development of muscle-invasive disease in >50% of cases by 2 years. For such high-grade disease or T1 tumours, intravesical immunotherapy with live attenuated Bacille Calmette–Guerin (BCG) is more effective. BCG instillation into the bladder stimulates a non-specific immune response with a proven reduction in tumour recurrence and prolongation in time to muscle invasion or metastasis. This is given as a course of 6 instillations on a weekly basis, and a small number of centres may continue with ‘maintenance therapy’ at 3–6-month intervals. The presence of Tis/high-grade disease or multifocal tumours refractory to immunotherapy or chemotherapy respectively is an indication for radical surgery. The overall 5-year survival rate for patients with superficial bladder cancer is currently around 95%.
Treatment of superficial tumours Over three-quarters of bladder cancers are superficial (Ta/T1) at time of presentation. It is usually possible to remove all visible tumour by endoscopic resection. However, following transurethral resection alone, 50–70% of patients with Ta/T1 tumours will have recurrence within 2 years. This is due either to instability of the urothelium or implantation of malignant cells into traumatized urothelium at the time of resection. To reduce this, many patients are treated adjuvantly with intravesical agents. These liquid agents are instilled into the bladder, kept in the bladder for 1–2 hours, and then voided. A single dose of intravesical chemotherapy (mitomycin C) immediately
SURGERY
283
© 2002 The Medicine Publishing Company Ltd
UROLOGY
Treatment of muscle-invasive tumours Approximately 20% of new cases already have tumour invasion into the detrusor muscle at diagnosis. Invasive bladder cancer has a 3-year survival of less than 5% in untreated cases. Furthermore, these tumours cannot be eradicated by transurethral resection alone or by intravesical therapy. Definitive treatment is either by radical surgery (cystectomy) or radical external beam radiotherapy. In these cases transurethral resection provides diagnostic and grading/staging information only.
on disease stage. The 5-year survival rates are 85% for T2 cancers, 55% for T3 and less than 25% for those with stage T4. SCC and adenocarcinoma Both these tumours are radio-resistant. The primary treatment of SCC is radical surgery but, despite this, the prognosis is poor and, even with the addition of adjuvant radiotherapy and chemotherapy, the 5-year survival remains at only 45–50%. Adenocarcinoma is treated by open excision, either partial cystectomy if the tumour location allows, or by radical cystectomy and urinary diversion/reconstruction.
Radical radiotherapy: following appropriate staging and planning investigations, invasive bladder cancers can be treated with a course of radiotherapy (64 Gy in 32 fractions). Radiotherapy has the advantage of bladder preservation, but may be associated with frequency and urgency along with future bladder contracture. It is relatively contraindicated in those patients with small bladder capacity (<300 ml) or pre-existing irritative lower urinary tract symptoms. Fifty percent of patients will exhibit a complete response to radiotherapy. Following irradiation, endoscopic surveillance is resumed. In the event of recurrent or refractory tumour, salvage cystectomy may be contemplated. This is technically more difficult than primary cystectomy due to radiation fibrosis, and generally precludes bladder reconstruction.
Metastatic bladder cancer Metastatic bladder cancer has a dismal prognosis, the mean survival being 6–12 months. Treatment is targeted primarily at symptom palliation. This may involve local tumour resection or palliative radiotherapy to control haematuria. Symptoms from metastases can be palliated with irradiation to bone or soft tissue. Involvement of palliative care services is frequently useful. Unfortunately, metastatic TCC is relatively chemo-resistant. Combination therapy with methotrexate, vinblastin, adriamycin and cisplatin (M-VAC) has shown a complete response in up to 20% of patients. However, this is a toxic combination (in one series the mortality of treatment was 4%) and long-term survivors are few. Future perspectives Bladder cancer is a common disease and treatment is determined primarily by whether the tumour is superficial or invasive. Therapy for the former is primarily endoscopic with or without intravesical agents. Muscle-invasive disease requires radical therapy. It is important to be familiar with the recurrent nature of superficial bladder cancer and to identify the factors that may predict progression to muscle invasion. u
Radical cystectomy: primary radical cystectomy has become the treatment of choice in bladder cancer invading the muscle. Preoperative assessment of general fitness and cardiorespiratory status is an important consideration before such major pelvic surgery. In males, a cystoprostatectomy +/- urethrectomy: the en bloc removal of the bladder, prostate, seminal vesicles, perivesical fat and pelvic peritoneum is performed. In females, an anterior pelvic clearance (en bloc removal of the bladder, anterior vaginal wall (including urethra), ovaries, uterus and pelvic peritoneum) is carried out. As part of radical surgery for bladder cancer it is routine to perform a pelvic node dissection. This is generally done to provide prognostic information, although there is emerging data to suggest a survival advantage in the presence of micrometastatic disease. Historically, the standard reconstruction after total cystectomy has been to form an incontinent urostomy where a conduit of ileum is anastomosed to the ends of the ureters and brought out as a stoma in the right iliac fossa. However, if the primary tumour is away from the bladder neck, the patient may be offered an orthotopic bladder reconstruction as an alternative to a urostomy. In this procedure, a neobladder is fashioned from a length of detubularized small or large bowel mobilized on its pedicle, which is then transformed into a cylindrical or spherical shape, with a resultant 33–50% increase in volume. The ureters are implanted into this and the apex anastomosed to the urethra. This avoids a stoma with the consequent benefits for body image and, with motivation and education, the patient is able to achieve continence. In the event of a urethrectomy being necessary, a final option is that of a continent urinary diversion, where a similar reservoir is formed from bowel, but connected to skin level by a catheterizable stoma incorporating a valvular mechanism. The prognosis in muscle-invasive bladder cancer is dependent
SURGERY
FURTHER READING Cohen S M, Johansson S L. Epidemiology and etiology of bladder cancer. Urol Clin North Am 1992; 19(3): 421–8. Enstoff M S, Heaney J A, Peschel R F. Urological Cancer. Oxford: Blackwell Science, 1997. Kamat A M, Lamm D L. Intravesical therapy for bladder cancer. Urology 2000; 55(2): 161–8. van der Meijden A P. Bladder cancer. BMJ 1998; 317(7169): 1366–9.
284
© 2002 The Medicine Publishing Company Ltd