BLADDER CANCER

Epidimiology
Bladder cancer is the second most common genitourinary malignancy after prostate cancer. In 1996, the American Cancer Society estimated there were 52, 900 new cases of bladder cancer in this country and 11,700 deaths. The disease is more common in males than in females (3:1), and the peak age is 60 to 70 years.

Thirty to forty percent of all bladder cancers may be directly attributed to cigarette smoking. Exposure to aromatic amines in the chemical and dye industries, as well as abuse of the pain killer phenacitin, have also been linked to the development of bladder cancer.

Clinical Presentation
Patients with bladder cancer typically present with painless blood in the urine (gross hematuria) or less commonly with microscopic hematuria. Some may have irritative symptoms including urinary urgency, frequency, and burning.

Diagnostic testing should include an x-ray test called an intravenous pyelogram (IVP) or a retrograde pyelogram to evaluate the kidneys and ureters. Most bladder tumors can be identified by using a small telescope called a cystoscope. Cancer cells may also be detected in the urine through a urinary pap test (cytology) or by identifying abnormalities of cellular DNA content using flow cytometry.

In the case of more advanced tumors, additional imaging studies are required to rule out cancer spread (metastasis). This typically includes a CAT scan of the abdomen, pelvis, and chest. A bone scan may be ordered as well.

Pathology
Transitional cells line the inner layer of the bladder, ureters, kidneys, and part of the urethra. Ninety five per cent of transitional cell carcinomas arise from the bladder. Only 10% of bladder cancers are nontransitional cell cancers and include sarcomas as well as squamous, adeno-, and small cell carcinomas. These will not be discussed further.

Staging and Prognostic Indicators
The stage of extent of disease is an important prognostic factor, as is tumor grade, ploidy, and over expression of the P53 gene. Seventy per cent of bladder cancers are superficial (contained within the mucosa or lamina propria of the bladder) at the time of diagnosis. These cancers often recur following treatment, but 80% never progress to a more invasive stage. Long term survival is over 80%. Thirty per cent of bladder cancers present with invasion into the muscle wall or are metastatic (into the lymph nodes or other organs).

TNM system for staging bladder cancer.

T:primary tumor

T0 No tumor present

Tis Carcinoma in situ

Ta Papillary tumor limited to mucosa

T1 Extension into but not beyond lamina propria

T2 Invasion into superficial muscle layer

T3a Invasion into deep muscle layer

T3b Invasion into perivesical fat

T4a Invasion into adjacent organ (prostate, vagina, uterus)

T4b Fixed to pelvic or abdominal wall

TX Minimum requirements to assess primary tumor not met

N: lymph node

N0 No evidence of lymph node involvement

N1 Involvement of single homolateral regional lymph node

N2 Involvement of contralateral, bilateral, or multiple regional lymph nodes

N3 Involvement of regional lymph nodes creating a fixed mass

N4 Involvement of juxta regional lymph nodes

NX Minimum requirements to assess lymph nodes not met

M: distant metastasis

M0 No evidence of distant metastasis

M1 Evidence of distant metastasis

MX Minimum requirements to assess presence of distant metastasis not met

Treatment for Superficial Bladder Cancer (Ta,T1)
Complete transurethral resection most bladder cancers can be accomplished under anesthesia using a cystoscope. Follow-up involves interval cystoscopy, usually every 3-6 months for two years, then every 6 months until a patient goes 5 years without a recurrence. If no recurrent disease is noted on the first follow up cystoscopy, the recurrence rate drops to 20% vs. 80% if cancer is again found. Smokers may lower their risk for recurrence if they stop smoking.

Patients with multiple or incompletely resected tumors, high grade disease, carcinoma in situ (cis), and lamina propria invasion (T1), are at higher risk for relapse or progression. After transurethral resection, these patients are often treated with medications instilled into the bladder (intravesicle therapy). While several chemotherapeutic agents including mitomycin, thiotepa, and doxorubicin may decrease short term recurrence rates, only Bacillus Calmette-Guerin (BCG) has been documented to decrease progression and increase survival rates over transurethral resection alone.

BCG treatment is typically given weekly for six weeks via an urethral catheter. This is done in the office, and patients are asked to retain the medicine in the bladder for two hours. This is thought to cause an immune response that kills cancer cells. Side effects are generally irritative in nature and include hematuria (46%), burning (91%), frequency (90%), fever (24%), and fatigue (18%). These symptoms usually resolve, although more serious complications can occur in 5%, and life threatening problems in less than 1%.

Not all bladder cancers will respond to a six week course of BCG treatment. If persistent CIS or T1 disease is found, the risk of progression may be too great to avoid more aggressive treatment. Otherwise, up to 50% may respond to a second six week course of BCG. Long term remission rates may also be higher if maintenance therapy is continued. This involves a three week treatment cycle at 3, 6, 12, 18, and 24 months. Those who do not respond to BCG may in some cases respond to mitomycin or interferon.

Treatment for Invasive (T2-T4) Bladder Cancer
Once cancer invades the muscular wall of the bladder, it is rarely curable with transurethral resection alone, with the occasional exception being a very select group with T2 disease. Other bladder sparing approaches may be possible for some patients. Partial removal of the bladder (partial cystectomy) can be considered for solitary tumors located alone the anterior wall. Radiation therapy alone has generally been ineffective with survival rates in the 20-30% range. Combined protocols using chemotherapy and radiation following transurethral resection have been used. However, long term survival rates with an intact bladder are under 50%.

Most patients with muscle invasive disease and not documented metastases will require surgical removal of the bladder and adjacent lymph nodes (radical cystectomy). For men, this also includes removal of the prostate and seminal vesicles. If extensive prostatic involvement is present, then removal of the entire urethra may be indicated as well. In women, the uterus, ovaries, urethra, and part of the vaginal wall are also included. Survival rates are dependent on the stage of disease; T2, T3a 60-80%, T3b 25-40%, and under 20% for T4. Survival following surgery alone for those with lymph node metastasis is also less than 35%.

While cystectomy is very effective for T1-T3 disease, results are poor for those with more advanced cancers. For many years preoperative radiation was given in an effort to decrease local recurrence rates. No survival advantage, however, has ever been demonstrated and this approach has largely been abandoned. While preoperative (neoadjuvant) chemotherapy has produced initial response rates of over 50%, a survival advantage with this strategy has also not yet been demonstrated, and for the most part this is being used in an investigational setting. Postoperative (adjuvant) chemotherapy for those at high risk for recurrence has also been investigated with a very questionable survival advantage at best.

Urinary Diversion
After the bladder is removed, a segment of intestine is fashioned to store urine. The least complicated and most reliable diversion is called an ileal conduit and was first described by Bricker in the 1950’s. The ureters are secured to a segment of small instestine (ileum) that is brought to the abdominal skin. The skin site is called a stoma and patients must wear an external drainage bag to collect urine. This in concealable under clothing and should not deter an active lifestyle. The ileal conduit is still the most common form of urinary diversion.

Continent stomas can also be made that do not require an external appliance. A larger bowel segment using either ileum alone (Kock pouch) or an ileal cecal segment (Indiana pouch) is used and must be drained every 4-6 hours with a urinary catheter. If urethrectomy is not done, a continent diversion (hemikock, Studer pouch etc.) can also be attached to the urethra, creating a more anatomical and natural diversion. These diversions are only appropriate, however, for motivated patients who are willing to accept a potentially higher complication and reoperation rate.

Treatment for Recurrent and Metastatic Bladder Cancer
Response rates to single agent chemotherapy are in the range of 10 to 30%. The highest response rates have been achieved with a combination of cisplatin, methotexate, vinblastine, and doxorubicin (MVAC). This combination has yielded response rates of 60 to 80% and complete remissions in up to 40%. Unfortunately, responses may often be short lived. Protocols using higher dose MVAC have not improved survival and have been associated with higher complication rates. Current studies are evaluating the combinations of paciltaxel with carboplatin and gallium nitrate with vinblastine and ifosfamide.

Conclusions
Despite the continued increase in the incidence of bladder cancer (36% over the last decade), mortality has decreased 8% since peaking in 1985. This may be related to the increased use of BCG for high risk superficial disease and early cystectomy for those with muscle invasive tumors. Continent urinary diversion may improve the quality of life for those undergoing radical surgery. More effective and less morbid chemotherapy regimens must be found for locally advanced and metastatic bladder cancer.