Bladder cancer accounts for 7% of all cancers. The man is the 4th leading cause of illness (7%) after prostate, lung and colorectal. It is estimated a total of 136,000 new cases annually. The annual rate of incidence is 32 / 100,000 in men and 9 / 100,000 women and the mortality rate is 9 / 100,000.
In Romania the estimated incidence for 2000 was 16.47 to 100,000 inhabitants and the mortality rate 5.15 per 100,000 inhabitants.
1. Smoking is responsible for about 65% in men and 30% women in cases of bladder cancer in the population in developed countries. The risk associated with cigarette smoking on smoking is due to the presence of aromatic amines including bezidine, 4-aminobiphenyl, 2-naphthylamine and 4-chloro-ortho-toluidine.
2. Occupational exposure to carcinogenic chemicals, rubber, organic dyes, processing metals and exposure to aromatic amines correlate with a high risk of bladder cancer. The risk attributed to exposure at work ranges from 10% -20%
3. Drugs. Ciclofosfamide is an alkylating agent has been strongly linked to bladder cancer and consistent. Patients with non-Hodgkin lymphoma were treated with ciclofosfamide have had dose-dependent bladder cancer.
4. Chronic cystitis caused by Schistosoma hematobium plays an important role. The infection is responsible for about 10% of bladder cancer cases in developed countries and 3% of all cases of bladder cancer. The areas mainly affected are Iraq, Egypt and Southeast Africa. In these areas Schistosoma eggs are frequently found in association with squamous cell cancers than transitional cell cancers.
5. Diet rich in vegetables and fruits probably protect their against bladder cancer.
6. Balkan nephropathy is associated with an increased risk for tumors of the renal pelvis and ureters
Screening can be performed by urinary cytology. Early diagnosis programs were suggested for people at high risk (large smoking, occupational exposure) or the elderly, but there is evidence for efficacy.
1. Transitional cell carcinoma represents 90-95% of all bladder tumors
2. Carcinoma in situ has a poor prognosis and is rarely associated with well-differentiated superficial bladder tumors and then gives a high rate of recurrence. It is associated more often with infiltrative tumors with higher grading. It may be asymptomatic in the initial phase and the signs often cause bladder irritation. At endoscopy velvety red patches appear.
3. Squamous cell carcinoma is found in 5-10% in developed countries and 75% in Egypt. About 80% of them are associated with infection with Schistosoma haematobium.
4. The adenocarcinoma appears in 1-2%
Signs and symptoms:
– Velvety red spots endoscopy bladder.
– Hematuria, bladder irritation signs: urinary frequency, dysuria, bladder tenesmus.
In advanced disease pain occurs in the pelvis, lower limb edema due to lymphatic and vascular compression.
1. Systemic Fibrinolysis
3. Neuromuscular Syndromes
Bimanual examination is recommended for diagnosis of bladder, intravenous urography, cystoscopy and biopsy, cytology.
Cytology is useful in poorly differentiated tumors and carcinoma in situ (CIS) for diagnosis and follow-up.
Biopsy is any suspicious lesion and tumor. Tumor biopsy must include the bladder wall.
The diagnosis is confirmed by histopathological examination.
For staging is recommended:
– Clinical examination, history, bimanual exam of the bladder under anesthesia,
– Cystoscopy with tumor biopsy,
– Intravenous urography,
– Chest X-ray,
– HL, hepatic and renal function tests,
– Abdominal ultrasound
– Abdominal and pelvic CT and MRI in tumors larger than 5 cm.
T – primary tumor
Tx – primary tumor cannot be assessed
T0 – no evidence of primary tumor
Ta – non-invasive papillary carcinoma (limited to urothelial layer)
T1s – transitional cell carcinoma “in situ” (payment tumor)
T1 – tumor invades corion (lamina propria)
T2 – Tumor invades muscle
T2a – Superficial invasion (domestic 1/2)
T2b – deep muscle invasion (external 1/2)
T3 – tumor invades the fat perivesical
T3a – microscopic fat invasion perivesical
T3b – fat macroscopic invasion perivesical
T4 – Tumor invades the pelvic organs, pelvic or abdominal wall
T4a – tumor invades the prostate, uterus, vagina
T4b – tumor invades pelvic or abdominal wall
Lymph node N
Nx – regional lymph nodes cannot be assessed
N0 – no regional lymph node metastases
N1 – Metastasis in a single lymph node £ 2 cm
N2 – metastasis or lymph node in several one
ganglion> 2 cm and <5 cm
N3 – metastasis in a lymph node> 5cm
M0 – no distant metastases
M1 – there are distant metastases
Std. N0 M0 your 0a
Std. Tis N0 M0 0i
Std. T1 N0 M0 I
Std. T2 N0 M0 II
Std. T3 N0 M0 III
Std. T4b N0 M0 IV
M0 Any T N1,2,3
Any T Any N M1
A. The treatment of superficial bladder cancer Ta – T1, N0, Mo
The goal of treatment is to eradicate bladder lesions by endoscopic approach. Intravesical therapy is administered to prevent relapses and disease progression.
Most patients are treated by transurethral resection of the tumor and less fulguration.
The survival to 5 years is 80% relapse is common and occurs in 71% – 80%
Relapse is treated by transurethral resection recurrence.
Transurethral resection is mandatory to obtain a pathologic diagnosis and staging correct. It involves removing the endoluminal portion of the lesion and biopsy of the bladder detrusor underlying. Specimens should be recorded and sent separately to the pathologist (endoluminal portion, deep muscle and fat perivesical wall). This allows the pathologist to define the depth of invasion and specify the category T. transurethral fulguration should be discouraged because it has no value in staging (Klan 1991).
Transurethral resection can achieve local control in about 30% of cases, due to the tendency to relapse in about 70%. Superficial bladder cancers(Ta) are usually low grade, rarely become invasive, but recur locally in nearly 50% of patients in 6-12 months. Not recommended therapy for patients with solitary tumor Ta, G1-2. A single instillation of chemotherapy after TURB reduces the risk of local recurrence by about 50% and the need for maintenance therapy for intermediate-risk tumors. (Bouffioux 1995).
Immediate intravesical chemotherapy applies to patients with Ta bladder tumors, low grade. For patients with Ta tumors, low grade G1-2 recommend a single administration of intravesical chemotherapy (not immunotherapy) close in the first 24 hours after resection. Intravesical chemotherapy reduces the risk of local recurrence by 12% induction It can be followed by 6 weeks. Mitomycin is usually used. The need for adjuvant chemotherapy depends on the presence or absence of risk factors for relapse: the size and number of tumors, tumor grading, concomitant CIS, lymphovascular invasion and the invasion of the prostatic urethra. Treatment should not be applied if extensive tumor resection was performed or if there is suspicion of bladder perforation.
Induction intravesical chemotherapy It begins 3-4 weeks after resection, maximum 2 inductions completely unanswered. The role of maintenance therapy is uncertain.
Induction intravesical chemotherapy is indicated in patients at high risk or progression with the intention of reducing the incidence of relapse for patients with increased risk of relapse:
– Ta tumors, High-grade (G3).
– T1 tumors that have invaded the lamina propria (corion)
– Tumors associated with CIS (carcinoma in situ), Tis
– Positive cytology after resection
Adjuvant chemotherapy intravesical BCG is (immunotherapy), Mitomycin C 20 mg, 50-90 mg doxorubicin, gemcitabine 2 g.
Ta tumors, high grade papillary tumors are with an increased risk of relapse or progression to invasive disease. In the absence of muscularis mucosae in the specimen or in case of incomplete resection means repeat resection. Adjuvant intravesical therapy is recommended with BCC. Mitomycin can also be used.
T1 tumors are tumors that invade the subepithelial connective tissue or lamina propria. They have an increased risk for relapse or disease progression. In patients with increased risk of relapse (absence of muscle specimen, large tumor, multiple tumors, lymphovascular invasion) means repeat resection. After tumor resection is recommended adjunctive therapy with intravesical BCC. In this group there is a high risk of relapse CATEGORY: multiple tumors, lymphovascular invasion or relapse after therapy with BCC.
For these patients would recommend cystectomy instead of repeating resection. If after repeated resection is recommended BCC recurrence found or cystectomy.
Tis tumors. Recommended treatment is resection followed by intravesical therapy with BCC. It is administered once a week for 6 weeks to 3 months re-evaluation. For support – Mitomycin BCC.
Intravesical immunotherapy induction It begins 3-4 weeks after resection. Discontinue if there is traumatic catheterization, bacteriuria, hematoria macroscopic, systemic or local persistent symptoms. It manages up to 2 inductions completely unanswered. There would be benefits from maintenance therapy.
Relapse after therapy
-After TURB Resection. Endovesical relapse following resection is treated by resection and new adjuvant intravesical therapy.
-After Intravesical treatment. Patients who relapse or if the disease persists after intravesical therapy can receive a new intravesical cure of Mitomycin or CCB. Do not administer more than 2 intravesical therapy cures. If after the second control residual disease cure exists of 3 months is recommended a new endovesical resection. If there is residual disease after TURB intravesical chemotherapy is recommended with another chemotherapeutic agent as an alternative to cystectomy. Patients who are not candidates for cystectomy may be proposed chemoradiotherapy. Patients with complete response to 3 months control to the BCC maintenance therapy -optional.
-Based on cytology result. In patients with positive cytology but negative endoscopy selective bladder biopsy is recommended. If the biopsy is positive selective recommend BCC BCC maintenance intravesical if there is control the complete response at 3 months. For patients with incomplete response is recommended cystectomy or another chemotherapeutic agent or participation in a trial.
B. Treatment carcinoma in situ (CIS)
The choice treatment consists in the administration of intravesical BCG. Complete remission was obtained in 70% with the survival time of 39 months. Treatment consists of weekly administration for 6 weeks BCC. Re-evaluate in 3 months.
One can administer 40mg intravesical mitomycin C, doxorubicin 50-90mg if not tolerate BCC.
In patients who do not respond to BCG or chemotherapy is recommended cystectomy other.
Intravesical chemotherapy or intravesical immunotherapy
Administration to begin immediately or 3-4 weeks after tumor resection. The user agent must run to stand intravesical 2:00. Administration is via the probe bladder.
1. Mitomicine C intravesical administered 40 mg weekly for 8 weeks, then monthly for 1 year. GM has high absorption and circulation is small.
2. Doxorubicin is used in doses of 50-90 mg / session has higher MW and is not absorbed into the systemic circulation. Cystitis occurs in 10-25% of patients.
3. Intravesical BCG (bacillus Calmette-Guerin) is a mycobacterium bovis strains obtained from stimulatory effect on the immune response. It begins 3-4 weeks after administration of tumor resection. It is given instillation / week for 6 weeks. As a side effect occurs in 5% cystitis, signs and symptoms that require treatment-tuberculosis. It is the most effective agent in the treatment of superficial bladder tumors.
C. The treatment of muscle invasive bladder cancer (T2 – T4)
TURB is the initial therapy for muscle invasive bladder disease. The role of TURB is to correctly identify the disease stage. Most tumors are intravesical urothelial high grade tumors. After the TURB treatment for tumors with bladder invasion there is a need for additional treatment.
1). Radical cystectomy with bilateral pelvic lymphadenectomy is the standard treatment. Radical cystectomy include excision of the bladder, prostate, seminal vesicles, prostatic urethra and bladder excision in women, the urethra, uterus, annexes and anterior wall of the vagina. Perivesical fat excision is associated, of the peritoneum and different procedures to deviate the ureters.
Radical cystectomy indications:
1. muscle invasive tumors
2. CIS not responding to intravesical therapy
3. low-grade superficial tumors that are diffuse multiple and recurrent and are not controlled by conservative therapy
4. shallow high-grade tumors refractory to conservative treatment.
In patients with metastatic lymph highlights histopathology stage ≥ T3b, perivascular lymphatic invasion are recommended 6 cycles of adjuvant chemotherapy.
The survival to 5 years T2 is 62-88% to 57-74% is T3a, T3b is for 29-57%
The mortality rate is 1 to 2%. Complications occur in 25 to 30%.
Preoperative radiotherapy administered to reduce recurrence rate.
Analysis of the available data suggests that preoperative radiotherapy is not an adjuvant to radical isolated surgery.
Preoperative radiotherapy for invasive bladder cancers has been abandoned by most urologists.
1. Cisplatin plus Gemcitabine is considered the new standard for advanced bladder cancer.
Cisplatin 70 mg / m2 / day i.v. on day 1
Gemcitabine 1 g / m2 iv 1,8,15 days.
Is repeated after 28 days. Complete remission in 21-28%. Overall response rate 60% and median survival of 14 months.
Methotrexate 30 mg / m2 / day i.v. days 1,15 and 22
Vinblastine 3 mg / m2 / day i.v. days 2,15,22
Doxorubicin 30 mg / m2 / day i.v. Day 2
Cisplatin 70 mg / m2 / day i.v. Day 2
It is given every 28 days
20-22% complete remission and overall response rate of 30-60%
28% 1-year survival and median survival 1 year
Line II: 1. Cisplatin 75mg / m2 iv Day 1
Taxol 135-175mg / m2 day 1 over 3 hours
Is repeated after 28 days
Total remission and complete remission in 79% to 21%
2. cisplatin 75mg / m2 iv Day 1
Taxotere 75mg / m2 iv Day 1
Is repeated after 28 days.
Complete remission in 26%, 60% response rate, medium survival 13 months
Neoadjuvant chemotherapy prior to cystectomy is recommended in patients with T2 and T3 tumors. A 5% improved overall survival and disease free survival by 9%.
Adjuvant chemotherapy is recommended in patients with lymph node invasion or T3 tumor patients.
2) radiotherapy followed by salvage cystectomy (in patients receiving radiation therapy was ineffective) is the standard treatment in some countries.
Primary radiotherapy should be reserved for patients with high surgical risk or those who want to maintain bladder personal reasons. Dose of 55-65 Gy is used, the daily fractionation of 2-2.5 Gy / day, 5 days a week.
For T2-T4 tumors when used radiotherapy alone, 5-year survival disease free was between 35-45% and overall survival of 23-40%.
D. Treatment of metastatic bladder cancer.
1). Cisplatin-based chemotherapy agent chemotherapy produced complete responses in 40% of patients and is standard therapy for bladder cancer with lymph node metastases.
The most commonly used chemotherapy regimens are: M-VAC and Cisplatin plus gemcitabine.
2). Surgical treatment of large tumors is recommended fulguration bleeding, which causes uncontrollable or severe irritative symptoms. Occasionally, depending on the symptoms can recommend palliative cystectomy and urinary deviation.
3). Radiation therapy improves the bleeding in 50% of patients and local pain in the areas of bone invasion.
1. TNM tumor stage. Muscle invasive carcinoma has a poor prognosis with a 5 year survival of 20-50%.
2. histological markers
v Squamous cell carcinoma and adenocarcinoma have a worse prognosis than transitional cell carcinoma.
v node invasion is associated with a poor prognosis, with a 5-year survival of 0% -20%.
lymphatic invasion and perivesical you have a poor prognosis.
v The histology. Poorly differentiated tumors are associated with an increased relapse rate. The survival to 5 years in low-grade tumors is 85% and 30% in high-grade tumors.
Pathology risk of relapse at 5 years Risk of muscle invasion
Ta, low grade 50% minimum
Ta, high grade 60% moderate
T1, 60% moderate low grade
T1, high degrees moderate-high 50-70%
Tis 50-90% higher
3. Molecular markers of prognosis:
– Aneuploidy and tetraploid
– Mutation gene p53, Rb gene overexpression.
Survival of five years depending on the pathological stage treatment for patients with:
q pT1 was 1%
q pT2 was 57%
q pT3 was 31%,
q pT4 was 24%.
Once the invasion of lymph node metastases than the bladder or there is overall survival at 5 years ranging from 4% to 35% in untreated patients.
In patients with distant metastases survival ranges from 6-9 months.
Tracking for patients with superficial bladder cancer is cystoscopy and cytology the urine of 3 months for 2 years, then every 6 months for 3 years and yearly thereafter for life.