Bladder cancer management is unchanged for many years. Radiotherapy is used increasingly in Europe, while in the US surgery is the primary treatment. Comparisons of large surgical and radiotherapy series suggest similar long term survival rates. Population studies do not appear to show survival differences related to mode of treatment. Bladder preservation therapy varies from a low of 10% in the US to 25% in Sweden to 50% in the UK. A larged randomized UK study suggest taht radical radiotherapy with chemo-sensitization (low dose chemotherapy or hypoxia targeting agents) is effective and well tolerated by elderly patients. Long term functional outcomes are excellent as well.
Bladder cancer is a major cause of morbidity and mortality. Median age at diagnosis is above 70 years, tumors are frequently tobacco related and patients may have signficant medical co-morbidity, making them less than idea operative candidates. There has been a documented increase in bladder cancer rates in patients older than 80 from about 13% to 24%. 75-80% are male, reflective historical tobacco use trends. Squamous cell cancers occur in the Nile Valley and are more associated with schistosomiasis. Aromatic amines, polycyclic aromatic and chlorinated hydrocarbons, arsenic cyclophosphamide exposure are implicated in urothelial cell cancers.
Most cases of non-muscle-invasive bladder cancer have high recurrence rates but are rarely lethal. The initial treatment is generally TURBT and observation. About 10-20% progress to muscle invasive disease which can metastasize. Up to 21% of Ta and 49% of T1 disease will die from bladder cancer. Thus, once diagnosed, lifetime surveillance is important.
Factors predicting progression have led to an EORTC bladder cancer calculator which quantifies risk based on tumor characteristics.
Muscle invasive bladder cancer has a poor prognosis due to a high rate of occult metastases at the time of diagnosis. There is a high rate of death from metastases after successful surgery. Reported 5 year survival rates with radiotherapy or surgery are quite similar at 45% - 50%, despite higher pelvic recurrence rates after radiotherapy. These data suggest prognosis is more driven by the presence of occult metastases or alternatively tumor related factors such as stage and grade.
Less than 10% present with metastatic disease. Most patients with mets have had prior treatment and carry a very poor prognosis. Overall survival is unclear as most cases are treated primarily palliatively, rather than as potentially curative cases. There are good data on outcomes with chemotherapy. In extensive randomized studies of the 1980s and 1990s, CDDP based regimens have been shown to be superior over CDDP alone or other combinations without CDDP. MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) and GC (Gemcitabine/CDDP) have been shown to be better. Median survival is 12 to 18 months depending on the extent of disease.
TCC behaves as a multifocal disease, with multiple primary tumors and frequent recurrences anywhere within the urothelial tracts. This may arise from field cancerization with exposure to carcinogen precursors. An alternate theory is that a transformed group of cells propagates throughout the urothelial tissue resulting in multiple tumors through shedding. Studies have shown that TCC multifocal sites are frequently monoclonal or oligoclonal. Both field cancerization and clonicity may be involved in TCC.
90% in the US are TCC, the remainder are half squamous cell which is often poorly differentiated and related to infectious processes common in Africa. Small cell cancers are extremely sensitive to treatment and are treated with bladder preservation following the same protocols as lung treatments.
Typical signs are painless hematuria, infection and urgency or frequency, initially transient then with increased frequency over time.
Initial presentation includes a clinical assessment, full CBC and biochemistry, PSA (males), urine cytology, cystoscopy, imaging (CT, US, IVP). Patients with identified tumor on cystoscopy will require tissue confirmation and staging workup.
Staging includes an EUA and TURBT, with the presence or absence of a mass after TURBT an important prognostic factor. Maximal TURBT that completely clears the tumor is good. But a less than complete TURBT is predictive of unsuccessful tumor clearance, muscle invasion, extravesicular extension, or both. The TURBT is the definitive staging study of the bladder. Note that muscle must be obtained with the TURBT to determine the extent, if any of muscle invasion. Bladder T staging is based on both characteristics and invasiveness:
Grade is also predictive of invasion and spread. High grade (grade 3/3) lesions may require addtional imaging with CT. Muscle invasive disease requires nodal evaluation with CT or MRI of the Chest, Abdomen and Pelvis. If alkaline phosphatase is elevated a bone scan may also be indicated. Note that enlarged pelvic nodes may be reactive following TURBT and TURBT itself can cause reactive changes that on imaging could be suggestive of extravesicular extension. Hydronephrosis or adjacent organ invasion is likely to be a reliable indicator of tumor stage and are poor prognostic indicators.
Nodal staging is relatively straightforward: N0, N1: single node in the true pelvis (ie hypogastric, obturator, external iliac or pre-sacral), N2, multiple nodes in the true pelvis, N3 mets to the common iliac chains.
80% present with non-muscle invasive disease, staged Tis, Ta, T1. The gold standard for diagnosis is TURBT with adequate deep sampling of the detrusor muscle deep to the lesion to determine muscle invasion, if present. Recurrences after TURBT alone are found in 70% of patients under surveillance. 15% of these will progress to muscle invasion. Upper urinary tract assessment is required, either by IVP, CT urography or ultrasound. Resection is frequently incomplete with residual tumor risk as high as 50% in T1 disease. For non-muscle invasive bladder cancer, the risk is stratified into low, intermediate and high risk which will dictate recommended treatment.
Low risk disease is defined as single tumors < 3 cm grade G1 and staged Ta with no evidence of CIS. There is a 15% probability of recurrence and a < 1% probability of progression at 1 year. These can be followed with a cystoscopy at 3 months post excision and if negative, then a repeat cystoscopy in 6 months and annually thereafter.
Clinical Factors:
High risk tumors should be followed with 3 month interval cystoscopies for 2 years and 6 month interval cystoscopies for an additonal 5 years and then annually. Intermediate risk tumors may be followed similarly with a frequency between low and high risk tumors. Intermediate risk tumors have a 38% probability of recurrence and 5% risk of progression at 1 year. High risk have 61% risk of recurrence and 17% risk of progression at 1 year. CIS increases the risk to 54% for disease progression.
Patients with low risk can be observed. Patients with intermediate and high risk tumors without CIS can be observed at more frequent intervals. Patients with CIS should be offered intravesical immunotherapy with BCG once per week for 6 weeks followed by treatment every 3 weeks. Interval cystoscopies should be continued.