Clinical Practice Guideline

for

CARCINOMA OF THE BLADDER

Developed for the

Aerospace Medical Association

by their constituent organization

American Society of Aerospace Medicine Specialists

Overview: Bladder cancer is the fourth most common cause of cancer in males and affects men three times more frequently than women. Its incidence also increases with age, with 90% of cases occurring in individuals over 55-years-old. There are more than 60,000 new cases diagnosed annually in the US accounting for approximately 14,000 deaths. In addition, there are an estimated 500,000 patients in the US with a history of bladder cancer which makes its prevalence greater than that of lung cancer. Cigarette smoking is one of the most well known risk factors, increasing the risk 2-to-4 fold and is attributed to causing 50-66% of all bladder cancers in men. Unlike lung cancer, the risk for bladder cancer remains elevated for a long time after the member quits tobacco, which probably accounts for the rising incidence of disease noted in the past few decades. Bladder cancer is much less common in the African American population than in Caucasians, who have the highest rate in the US population.

Exposures to toxins such as in the textile dye and rubber tire industries are risk factors. Historically, these industries used β-naphthylamine, 4-aminobiphenyl, and benzidine all of which were unequivocally associated with bladder cancer. These chemicals have been banned, but the long delay between exposure and the development of malignancy makes it difficult to ascertain a definitive relationship for a whole host of other compounds which are still used in the chemical, dye and rubber industries. Chronic infection can also be a risk factor for bladder cancer. This is seen more commonly in under-developed countries and thought to be largely related to infection with schistosomiasis.

As with most cancers, prognosis is largely, but not entirely determined by stage and grade; other factors include location of the lesion in the bladder, number of lesions and maximum diameter of the largest tumor. The American Joint Committee on Cancer staging system (also known as TNM) is the most widely used system for staging (see Table 2), while the World Health Organization and International Society of Urologic Pathologists published a recommended revised consensus classification system in 2004 (see Table 3). The upper urinary tract should be imaged during initial work up as 5% of bladder cancers can have an upper tract lesion.

Urothelial carcinoma, also known as transitional cell carcinoma, is the most common pathologic subtype of bladder cancer and is seen in over 90% of all tumors. Squamous cell tumors account for about 5% of all cases and adenocarcinomas are about 1% of the total. The presenting symptom in the majority of cases is hematuria which can be either continuous or intermittent. Therefore, the American Urologic Association (AUA) recommended in 2001 that all patients with hematuria, particularly those without evidence of infections, stones or other common causes, undergo cystoscopy and upper tract imaging. The physical exam is unremarkable in bladder cancer patients, particularly those with nonmuscle invasive disease, (which accounts for 70% to 75% of patients). As our population is relatively young, most of the cases will be early in the lifecycle and more likely to be non-muscle-invasive in nature.

Table 1: American Joint Committee on Cancer Bladder Staging System

Stage	Clinical Tumor Stage
TX	Tumor cannot be assessed
Ta	Non-invasive papillary carcinoma
Tis	Carcinoma in situ
T1	Tumor invades lamina propria
T2	Tumor invades muscularis propria
T2a	Invades superficial muscularis propria (inner half)
T2b	Invades deep muscularis propria (outer half)
T3	Tumor invades perivesical tissue/fat
T3a	Invades perivesical tissue/fat microscopically
T3b	Invades perivesical tissue/fat macroscopically (extravesical mass)
T4	Tumor invades prostate, uterus, vagina, pelvic wall, or abdominal wall
T4a	Invades adjacent organs (uterus, ovaries, prostate stroma)
T4b	Invades pelvic wall and/or abdominal wall
	Regional Lymph Nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in a single lymph node, 2 cm or less in greatest dimension
N2	Metastasis in single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension
N3	Metastasis in a lymph node more than 5 cm in greatest dimension
	Distant Metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis

Table 2 – AJCC Stage Grouping for Bladder Cancer.

Stage	Primary Tumor (pT)	Regional Lymph Nodes (N)	Distant Metastasis (M)
0a	Ta	N0	M0
0is	Tis	N0	M0
I	T1	N0	M0
II	T2a	N0	M0
	T2b	N0	M0
III	T3a	N0	M0
	T3b	N0	M0
	T4a	N0	M0
IV	4b	N0	M0
	Any T	N1	M0
	Any T	N2	M0
	Any T	N3	M0
	Any T	Any N	M1

Table 3: WHO Grading Classification of Nonmuscle Invasive Urothelial Neoplasia

Hyperplasia (flat and papillary)

Reactive atypia

Atypia of unknown significance

Urothelial dysplasia

Urothelial carcinoma in situ

Urothelial papilloma

Papillary urothelial neoplasm of low malignant potential

Nonmuscle invasive low-grade papillary urothelial carcinoma

Nonmuscle invasive high-grade papillary urothelial carcinoma

Treatment is largely dependent upon the grade and stage, with more invasive treatment as the grade and stage increase. Therapy can range from transurethral resection of a bladder tumor (TURBT) to radical cystectomy and resection of affected structures. Often, intravesical therapy is used as an adjunct to tumor resection and or as a prophylactic measure to prevent recurrence.

For non-muscle invasive tumors (defined as stages Ta, Tis, and T1), the initial treatment is a complete TURBT and an examination under anesthesia (EUA) to rule out a palpable mass which would suggest muscle invasive disease. For T1 tumors, up to 30% of cases will be understaged by TURBT, so repeat TURBT is recommended to decrease likelihood of actual understaging. The majority of these non-muscle invasive tumor cases will recur and up to 25% of these will progress, so rigorous surveillance and follow-up is mandatory. Intravesical therapy (instilled into the bladder via catheter) is generally used in the adjuvant setting, to prevent further recurrence. Chemotherapy or immunotherapy agents can be used in this manner. Bacillus Calmette-Guérin (BCG) and mitomycin C are widely used as an intravesical immunotherapy agent but other agents can be used as well. A key point with these agents is that patients often have no side effects for several cycles, and then 90% will develop cystitis and up to than 25% will develop fever, malaise, and hematuria. These symptoms generally resolve quickly after completion of therapy, which is usually administered once/week for 6 weeks.

For tumors that are invasive (T2 and above) and for some high grade T1 tumors, radical cystectomy is the recommended therapy, with consideration of neoadjuvant chemotherapy and radiotherapy, depending on stage of disease at presentation and the patient’s overall health status. Bladder preservation or sparing treatment using primary chemotherapy and external beam radiotherapy is an option in selected patients with T2 and T3a urothelial carcinomas, but is associated with higher rates of recurrence and disease specific mortality. Often this approach is reserved for patients who are medically unfit for major surgery or for those seeking an alternative treatment course.

Because of a fairly high risk of recurrence for all grades and stages, there will be a lifetime need for scheduled follow up evaluation. In general, all patients with non-invasive disease can expect a recurrence rate of 50%, but this rate is higher in those with high grade disease. Follow up is recommended in accordance with American Urological Association (AUA) practice guidelines. Early after treatment, the patient may be required to undergo urologic evaluation (urinalysis, cytology, cystoscopy, +/- imaging and additional labs) every 3 months. After 2 years without recurrence, the recommendation is for annual exams indefinitely. Several urothelial malignancy markers have recently been approved by the FDA, but there is not sufficient evidence at this time for their routine use in detection of new disease or surveillance for recurrence. However, studies are ongoing.

Aeromedical Concerns: The aeromedical concerns are based more on the treatment and possible therapy complications than on the disease itself. If the aviator is off all treatment medications and is disease-free (considered to be in remission) and asymptomatic, he or she can be considered for a waiver. Due to a relatively high risk for recurrence, the flyer needs frequent follow up with their urologist. There is low likelihood that recurrence of non-invasive disease would cause sudden incapacitation.

Medical Work-up: Documentation for an aviator with bladder cancer starts with a good history to include all symptoms, pathology, stage, treatment, including date of last treatment, surveillance plan and activity level. Additionally, all cystoscopy/surgical reports along with pathology-confirmed histological diagnosis, as well as a current urinalysis and reports from all imaging studies are needed. Urology/oncology consults to include the quarterly tumor surveillance follow-up in accordance with National Comprehensive Cancer Network (NCCN) guidelines are necessary components as is confirmation the aviator does not require continued therapy (other than routine follow-up) and that he or she is free of physical limitations. Finally, if the aviator is military, a tumor board report may be required as are the results of the medical evaluation board.

Aeromedical Disposition:

Air Force: History of bladder cancer is disqualifying for flying classes I/IA, II, and III. According to AFI 48-123, V3, A4.31.1.2, the “history, or presence of, malignant tumor, cyst or cancer of any sort” is disqualifying for aviators. Waiver can be considered in trained aviators six months after completion of treatment, in remission and if they are asymptomatic. For untrained aviators, a waiver can be considered after five years of remission if the patient is asymptomatic.

Army: Bladder cancer is disqualifying for Army aviation service by AR 40-501 and is discussed in the Army Aeromedical Policy Letter of that name. The aeromedical concerns and evaluation are similar between the Army and Air Force. A recommendation for waiver will be considered on an individual basis after initial localized therapy, provided the tumor is confined to the epithelium. Localized transitional cell carcinoma generally responds well to treatment. Muscle invasive disease may require more extensive resection, which often results in residual defects that are incompatible with aviation duties. Cystectomy or the requirement for repeated catheterization results in disqualification with only rare waiver recommendations.

Navy: A waiver request can be considered after initial therapy, provided the tumor is confined to the epithelium. Cystectomy or the requirement for repeated catheterization results in disqualification, with no waiver recommended

Civilian: Recertification for civilian airmen would require a current status of the airman every year for at least 5 years. An airman would be able to return to flying after a transurethral resection of a bladder tumor as soon as they were stable. If the airman was receiving intravesical instillation of a chemotherapeutic agent, they are usually told not to fly for 72 hours post instillation. If there are no side effects related to the instillation, then the airman could be grounded for the immediate time period surrounding the administration of the medication. Disease that has spread into the muscular layer would require a one-year observation period prior to considering medical certification. Spread of disease to the lymph nodes, contiguous tissues or distant sites would be disqualifying. The FAA has granted medical certification to airmen with ileal conduits. Initial medical certification really depends on the extent of the disease and the type of maintenance treatment. Follow-up testing requirements usually depend on the extent of disease but generally is yearly status reports, results of cystoscopy, CT scan of abdomen and chest.

For military aviators, an aeromedical summary should include (1) initial presentation, (2) all cystoscopy/surgical reports, (3) Armed Forces Institute of Pathology confirmation of histology, (4) chronology of therapy and results, (5) remarks that patient is in remission, off all medications, and free of physical limitations, (6) remarks concerning future follow-up including Tumor Board and oncology or nephrology recommendations. Upgrading of flying category requires full flying physical, CXR, contrast studies of entire urinary tract, and CT or MRI of the abdomen, pelvis, and any involved viscera. A bone scan is required if past history positive or suspicious bone pain warrants.

Waiver Experience:

Air Force: Review of AIMWTS database revealed 12 waiver requests. There was one FC I case which was actually an active duty navigator applying to UPT; he had a superficial tumor, but was disqualified due to the fact it was a FC I case. There were eight FC II cases and all were granted a waiver and three FC III cases, all granted a waiver. One of the FC III cases was for a young man who had a bladder rhabdomyosarcoma at age 2 and recovered well. The remaining 11 cases all appeared to be superficial tumors (not all discussed pathology).

Army: Since 1990 there have been 123,259 aviators of all types, including applicants enrolled in the Aeromedical Epidemiological Data Repository. Among them there have been 15 cases of bladder cancer in rated aviators, one in an applicant and 11 in non-rated aviators. Of those, only two rated and 3 non-rated aviators were disqualified.

Navy: Precise statistics are not available at this time.

Civilian: The current PATH CODE system in the FAA has some medical diagnoses that have several related medical conditions with the same code. This is one such condition. As of January 2010 there are 6 first-, 13 second-, and 96 third-class airmen that are currently issued with bladder cancer or tumor.

ICD9 Codes for Bladder Cancer
188	Malignant neoplasm of bladder
233.7	Carcinoma in situ of bladder

References:

Hall MC, Chang SS, Dalbagni G, et al., Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol, 2007; 178(6):2314-30.

Grossman HB, Soloway M, Messing E, et al. Surveillance for Recurrent Bladder Cancer Using a Point-of-Care Proteomic Assay. JAMA, 2006; 293(3):299-305.

Kirkali Z, Chan T, Manoharan M, et al., Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology, 2005; 66(6 Suppl 1): p. 4-34.

Pashos CL, Botteman MF, Laskin BL, and Redaelli A. Bladder cancer: epidemiology, diagnosis, and management. Cancer Pract, 2002; 10(6):311-22.

Montie JE, Clark PE, Eisenberger MA, et. al. Bladder Cancer, in Practice Guidelines in Oncology,. 2009, National Comprehensive Cancer Network.

Badawi AF, Mostafa MH, Probert A, and O’Connor PJ. Role of schistosomiasis in human bladder cancer: evidence of association, aetiological factors, and basic mechanisms of carcinogenesis. Eur J Cancer Prev, 1995; 4(1):45-59.

Parmar MK. Prognostic factors for recurrence and followup policies in the treatment of superficial bladder cancer: report from the British Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party). J Urol, 1989; 142(2 Pt 1):284-8.

Greene FL, Page DL, Fleming ID, et. al. AJCC Cancer Staging Manual. 6th ed. 2002, New York: Springer-Verlag.

Eble JN, Sauter G, Epstein JI, and Sesterhenn IA. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary and Male Genital Organs, 2004, Lyon.

Morey SS. American Urological Association issues guidelines on the management of bladder cancer. Am Fam Physician, 2000; 61(12): 3734, 3736.

O’Donnell MA. Treatment of non-muscle-invasive (superficial) bladder cancer. UpToDate. Online version 16.3, 1 October, 2008.

American Urological Association, Hematuria, in Medical Student Curriculum, A.U. Association, Editor, 2008.

Prepared by Drs. Ken Egerstrom and Dan Van Syoc

11/10/10