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Bladder Cancer

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Overview of epidemiology

Bladder cancer is a common disease worldwide. Incidence varies across the globe, with the highest burden of disease in developed countries. The less-developed countries are following closely, with increasing incidence as bladder cancer emerges as an important cause of morbidity and mortality all around the world. These observed disease trends are driven by both the ageing populations in developed nations as well as increasing exposure to environmental carcinogens in less-developed countries.

In published data, bladder cancer is consistently one of the top 20 cancers in both males and females. Age-standardized global incidence rates have been quoted as 2.5 per 100,00 in females and as high as 10.1 per 100,000 in males.

According to the World Health Organization, the single most important environmental risk factor for bladder cancer is tobacco use. Smoking is associated with a two- to three-fold increase in bladder cancer incidence compared with non-smokers. While the bladder itself is not directly exposed to tobacco smoke, it is well-established that polyaromatic hydrocarbons that circulate in the blood stream of smokers are largely responsible for the carcinogenic effects on the urothelium. Another risk factor that is worth mentioning as it contributes to bladder cancer incidence is occupational carcinogens. This is why underwriters must always be on high alert when dealing with certain occupations particularly if there is a classic history of hematuria.


Examples of such occupations are:

  • Dry cleaners
  • Painters
  • Paper production workers
  • Rope-and-twine industry workers
  • Dental workers
  • Physicians
  • Barbers
  • Beauticians

In developing countries, chronic bladder infection with Schistosoma haematobium or so-called bilharzia is an important risk factor for squamous cell carcinoma (SCC) of the bladder, especially in regions like Egypt where this parasitic infection is endemic. The risk factors that lead to cancer are:

  • Worm burden
  • Chronicity of infection
  • Host inflammatory response
  • Concentration of N-nitrosamines in urine 

Bladder cancer can also be directly correlated with other medical treatments, for example, previous pelvic radiation, and chemotherapy with cyclophosphamide, which increases the risk of bladder cancer via exposure to acrolein, a urinary metabolite of cyclophosphamide. Other cases that are at risk of bladder cancer are spinal cord injury patients that require long-term indwelling catheters, which have shown a multi-fold increase in the risk of developing SCC of the bladder. The mechanical/irritant effect of the in-situ catheter is deemed a likely pathophysiological mechanism.

In Western countries and the U.S., the life time probability of a white male developing bladder cancer is estimated at one in 25. The overall survival over eight years is 75% according to SEER data published in the Oncologist 2003, but males have a higher five-year survival rate by all stages compared with females.

It is worth mentioning that, in the developed world, the overall mortality associated with bladder cancer has been reduced significantly over the past two decades. This is attributable to several factors of which the most important are:

  • Tobacco control measures resulting in reduced smoker prevalence
  • Reduced occupational exposure to aromatic amines
  • Early bladder cancer detection and intervention

There is no strong association between genetic risk factors and bladder cancer. Smoking emerges as the single most important risk factor for this disease.

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Symptomatology

Up to 90% of cases present with painless sporadic gross hematuria. This blood in the urine is unpredictable and may disappear for weeks before reappearing. Other common bladder irritation symptoms are reports of frequency, urgency and dysuria. 

In more advanced cases of bladder cancer there may be complete anuria, chronic lower back pain, bone pain and cancer cachexia. In rare cases there might be a palpable fixed mass upon physical examination of the lower abdomen, and this is considered a sinister sign as it implies quite advanced bladder cancer. 

Investigations

The work-up of a bladder cancer patient involves urinalysis with resultant cytology and culture of the urine sample. Cystoscopy is considered the gold standard in bladder cancer diagnosis. The combined use of cystoscopy and endoscopic biopsy allows for direct visualization of the internal bladder wall with accurate sampling of abnormal looking lesions. This is important, as bladder cancer can be multi-focal. Typically the lesions that are visualized at cystoscopy are papillary formations or flat tumors along the transitional epithelium. 

Imaging studies of the upper urinary tract are an integral part of the hematuria workup. Computed tomography (CT) scans of the abdomen and pelvis with contrast are also recommended. Two commonly used alternative techniques are magnetic resonance imaging (MRI) and renal ultrasonography. A few centers still perform intravenous pyelography (IVP) for upper tract imaging. The IVP was once considered as the gold standard for diagnosis of bladder lesions but is being slowly replaced by more modern means of investigation. 

There are no specific blood tests or tumor markers for the diagnosis of bladder cancer. Several urinary tumor markers are commercially available; however, they are not diagnostic but rather an adjunct to imaging and direct visualization.

Bladder cancer staging 

From pathohistological specimens we know that bladder cancer is commonly found in the transitional epithelium, also known as urothelium, which forms the inner lining of the bladder. The commonest type of cancer in the bladder is transitional cell carcinoma, accounting for more than 90% of all bladder cancers. Other less-common types of cancer in the bladder are squamous cell carcinoma and adenocarcinoma. 

Over the years various bladder cancer staging/classification systems have been adopted and published in medical literature. The most-widely utilized is the American Joint Committee on Cancer staging with the corresponding TNM staging. 

The most-commonly diagnosed stage of cancer is early bladder cancer, i.e., non muscle invasive disease. These early cancers can be readily identified after cystoscopy and biopsy of suspicious lesions in the bladder wall. Detection is through direct visualization of abnormal lesions in the urothelium. 

Treatment 

Smoking cessation is an important part of the management of bladder cancer. Continued use of tobacco is undesirable. 

Superficial bladder cancers or early-stage (non-muscle invasive) cancers are managed surgically with transurethral resection. A transurethral resection (TUR), also known as a transurethral resection of the bladder tumor (TURBT), is the most common surgical treatment. TURBT is minimally invasive and does not leave a clearly visible scar on the abdomen. This means that TURBT cases will retain their bladders with respective preservation of bladder functions. 

After eradication of cancer, the biggest challenge with bladder cancer management is recurrence. This is one of the most persistent cancers and, despite optimal surgical resection, has a high risk of recurrence of up to 80% of all cases having at least one recurrence. Factors associated with recurrence can be outlined as:

  • Tumor size >15mm
  • High-grade cytology wash out
  • Positive resection margins
  • Short interval between surgery and first recurrence

The treatment approach in response to recurrent bladder cancer includes intravesical therapy with various chemotherapeutic agents and immunotherapy. A commonly used duo of chemotherapy agents for this purpose is mitomycin and thiotepa. The immunotherapy that is the most utilized is Bacillus Calmette-Guerin (BCG). While BCG is effective, it has a side effect profile that is poor, which has encouraged the exploration of newer agents that will hopefully have much better tolerability.

More-aggressive disease can be treated with a partial cystectomy or a radical cystectomy. A radical cystectomy is major abdominal surgery that entails the surgical excision of the complete bladder, adjacent pelvic lymph nodes and part of the urethra. In males this may also include the prostate, vas deferens and seminal vesicles. In females this procedure may include removal of the cervix, uterus, ovaries, fallopian tubes and the upper part of the vagina. 

Guidelines for follow-up 

The high rate of disease recurrence and disease progression in early bladder cancer underscores the need for careful follow-up studies. As outlined above, most cases may still have an intact bladder so the number of patients under surveillance is quite high. 

The 2011 EAU guidelines include schedules for follow-up cystoscopy, urinary cytology and imaging in patients with Ta and T1 tumors. This schedule depends on the risk of recurrence and possible progression. For follow-up in patients with no visible tumor in the bladder but positive cytology, the guidelines recommend biopsies and investigation of extravesical locations. The NCCN 2012 guidelines further specify that cystoscopy and urinary cytology should be performed every 3-6 months for two years and then at increasing intervals as deemed appropriate by the attending practitioner. 

Prognosis

The most significant prognostic factors for bladder cancer are grade, depth of invasion, and the presence of CIS. In patients undergoing radical cystectomy for Stage III-IV bladder cancer, the presence of nodal involvement is the most important prognostic factor. Early bladder cancer without evidence of muscle invasion has a good prognosis, with five-year survival rates of 82-100%. 

As mentioned earlier, bladder cancer has the highest recurrence rate of any malignancy, so even though most patients with bladder cancer can be treated initially with organ-sparing therapy, most experience either recurrence or progression. Risk factors for recurrence and progression include the following: 

  • Female gender
  • Larger tumor size >15 mm
  • Multifocality of lesions
  • High tumor grade
  • Advanced stage of bladder cancer
  • Presence of carcinoma-in-situ

Advanced bladder cancer with metastasis has a poor prognosis. Published data shows a relative five-year survival of less than 15% for all Stage IV cancers.

Golden nuggets for underwriters 

  1. High index of suspicion if there is a combination of occupations that work with solvents and a classic history of hematuria
  2. Previous bladder cancer caries a high risk of recurrence so treatment dates are important
  3. Unsuccessful smoking cessation carries a poorer prognosis

Golden nuggets for claims assessment

  1. For critical illness claims, a cytology report is not enough to stage bladder cancer
  2. Terminal illness benefits are payable for cases that cannot be treated with radical cystectomy
  3. Early bladder cancer is not usually disabling but can result in a poor work attendance record

What’s new in bladder cancer? 

Telomerase levels can be measured in the urine samples of individuals with bladder cancer. This could become a modern form of non-invasive and cost-effective means of bladder cancer screening. There is currently ongoing research into refining the specificity and sensitivity of available urine assays for telomerase levels to detect the presence of bladder cancer particularly in asymptomatic patients. The new generation telomerase assays utilize variations like TeloTAGGG or with gold nanoparticles. The most likely probability is that these assays are unlikely to replace cystoscopy but may have a role in screening programs for sub-sets of high risk patients. To date no consensus guidelines have been published for clinical practice but this is one to watch in cancer underwriting! 


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RGA has made all reasonable efforts to ensure that the information provided in this publication is accurate at the time of inclusion and accepts no liability for any inaccuracies or omissions. None of the information or opinions contained in this publication should be construed as constituting medical advice.
Download "ReFlections Fall 2014"

The Author

  • Nontuthuzelo Thomas, M.D.
    M.B.CH.B.
    Chief Medical Research Officer (former)

    RGA South Africa

Summary

Bladder cancer is a common disease worldwide. Incidence varies across the globe, with the highest burden of disease in developed countries. This article examines observed trends, medical advances and underwriting implications. 
Download "ReFlections Fall 2014"
  • Bladder Cancer
  • medical innovation
  • mortality experience
  • mortality assumptions
  • medical advances
  • mortality trends
  • medical underwriting