The information below will serve to highlight some of the pertinent points of our discussion with patients newly diagnosed with bladder cancer. By no means will this information cover everything in our face-to-face discussion, but it can help patients as a reference guide management decisions. Please be aware that there are a lot of options and not every option is available for every patient.

In addition, as you will soon realize, most specialists who deal with Bladder cancer will naturally be biased towards the treatment modality they do best: surgeons for surgery, radiation oncologists for radiation, medical oncologist for chemotherapy etc.

This information is just a start, and we hope will help lead you ultimately to the treatment that is the best for you.

INTRODUCTION

Bladder cancer is a disease in which malignant (cancer) cells form in the tissues of the bladder. The bladder is a hollow organ in the lower part of the abdomen. It is shaped like a small balloon and has a muscular wall that allows it to get larger or smaller. The bladder stores urine until it is passed out of the body.

Urine is the liquid waste that is made by the kidneys when they clean the blood. The urine passes from the two kidneys into the bladder through two tubes called ureters. When the bladder is emptied during urination, the urine goes from the bladder to the outside of the body through another tube called the urethra.

There are three types of bladder cancer that begin in cells in the lining of the bladder. These cancers are named for the type of cells that become malignant (cancerous) :

Transitional cell carcinoma: Cancer that begins in cells in the innermost tissue layer of the bladder. These cells are able to stretch when the bladder is full and shrink when it is emptied. Most bladder cancers begin in the transitional cells.

Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells that may form in the bladder after long-term infection or irritation.

Adenocarcinoma: Cancer that begins in glandular (secretory) cells that may form in the bladder after long-term irritation and inflammation.

Cancer that is confined to the lining of the bladder is called superficial bladder cancer. Cancer that begins in the transitional cells may spread through the lining of the bladder and invade the muscle wall of the bladder or spread to nearby organs and lymph nodes; this is called invasive bladder cancer.

Bladder transitional cell carcinoma makes up nearly 90% of all primary bladder tumors. In the United States, it is the fourth most common cancer in men and the eighth most common cancer in women. Approximately 70% of patients with bladder cancer initially present with superficial disease that has not invaded through the lamina propia. However, one fourth of patients will either present with or subsequently develop muscle invasive disease. If left untreated, over 85% of patients will die of the disease within 2 years of diagnosis. Despite an early and aggressive approach toward high-grade, invasive bladder cancer, nearly 25% of patients demonstrate pathologic evidence of lymph node metastases at the time of cystectomy. As a result, high-grade or muscle invasive bladder cancer is typically regarded as a potentially lethal disease with high propensity for spread despite definitive therapy.

The clinical spectrum of bladder cancer can be divided into 3 categories that differ in prognosis, management, and therapeutic aims.

The first category consists of noninvasive tumors, for which treatment is directed at reducing recurrences and preventing progression to a more advanced stage. The second group encompasses the invasive lesions, and the goal of therapy is to determine if the bladder should be removed or preserved without compromising survival, and to determine if the primary lesion can be managed independently or if patients are at high risk for distant spread requiring systemic approaches to improve the likelihood of cure. The critical concern of therapy for the third group, consisting of metastatic lesions, is how to prolong life.

NON-MUSCLE INVASIVE TUMORS

Divided into noninvasive papillomas or carcinomas (Ta), those invading the lamina propria (T1), and CIS. These tumors have previously been referred to as superficial or non-invasive. In some cases, a papillary or T1 lesion will be documented as having an associated in situ component (Tis). Standard treatment in these cases is repeat transurethral resection. However, depending on the depth of invasion and grade, intravesical therapy may be recommended.

I am suggesting this based on the estimated probability of recurrence (i.e.new tumor formation within the bladder) and progression to a more advanced, usually invasive stage, which are events that should be considered independently. Cystectomy is rarely considered for a Ta, G1, or G2 lesion. Intravesical therapy (solution instilled into the bladder) is used in 2 general settings: as prophylactic or adjuvant (prophylactic) therapy after a complete endoscopic resection or, rarely, as therapy with the goal of eradicating residual disease that could not be completely resected.

PAPILLOMA, TA, G1, OR G2

Transurethral resection without intravesical therapy is the standard treatment for Ta, G1 and Ta, G2 tumors. Because patients diagnosed with these tumors have a relatively high risk for recurrence, I also recommend a single dose of intravesicular chemotherapy (not immunotherapy) within 24 hours of resection. Close follow-up is needed, although the risk for progression to a more advanced stage is low. As a result, I advise patients to undergo a cystoscopy at 3 months initially, and then at increasing intervals with upper tract imaging (CT or retrograde pyelograms) at least once a year as up to 4% of patients will develop either ureteral or renal pelvis recurrence. If no recurrences develop during the first year, the interval between evaluations can be increased. Patients with a documented recurrence are treated with TURBT and adjuvant therapy based on the stage and grade of the recurrent lesion, and are then followed up at 3-month intervals. Intravesical therapy is recommended for patients with a history of recurrences.

TA, G3 DISEASE

Tumors staged as Ta, G3 lesions are considered high-grade papillary tumors with a relatively high risk for recurrence and progression towards more invasiveness. Therefore, in addition to observation, they are treated with intravesical bacillus Calmette-Guerin (BCG) or mitomycin (MMC).

CIS

Primary carcinoma in situ or CIS (Tis) is a high-grade lesion that is believed to be a precursor of invasive bladder cancer. Standard therapy for this lesion is a complete endoscopic resection followed by intravesical therapy with BCG. This therapy is generally given once a week for 6 weeks, followed by a rest period of 4 to 6 weeks, with a full reevaluation at week 12 (i.e., 3 months) after the start of therapy. Patients with Tis who have recurrent or persistent disease at the 12-week (3-month) evaluation can be given a second course of BCG or MMC induction therapy or offered radical cystectomy. If they do respond to a course of BCG then mainainence therapy is recommended as this has been shown to prevent recurrences. The optimal maintenance schedule and duration has yet to be determined. However, the best available evidence supports the use of the SWOG (Southwest Oncology Group) regimen which involves a six-week induction course of BCG followed by a three-week maintenance course at 3, 6, 12, 18, 24, 30,and 36 months (if tolerated by the patient). This regimen was used in, by far, the largest trial that demonstrated the benefit of maintenance BCG therapy.

T1

T1 lesions, those invading lamina propria, are considered to be potentially dangerous (usually T1, G2 or T1, G3) and have a high risk for recurrence and progression. They are treated with a complete endoscopic resection followed by intravesical therapy (this is optional for G1 or G2 lesions).

LOW-RISK DISEASE

After undergoing the initial transurethral resection, patients with low-risk disease are observed or undergo intravesical treatment with BCG or MMC. Follow-up includes urinary cytology and cystoscopy recommended at 3-month intervals for the first 2 years, repeated at 6 month intervals over the next 2 years, and annually thereafter.

HIGH-RISK DISEASE

Patients with high-risk disease (T1, G3) can be treated with a course of BCG, MMC, or radical cystectomy after a certain and satisfied resection. If the complete resection is uncertain because of the tumor size and location, no muscle is shown in the specimen, lymphovascular invasion has occurred, or inadequate staging is speculated, repeat resection of tumor or cystectomy followed by intravesical therapy with BCG or MMC is recommended. Evolving data suggest that early cystectomy may be preferred if residual disease is found, because of the high risk for progression to a more advanced stage. If high-risk disease is managed conservatively and does not respond to BCG, a cystectomy should be performed. Also, pathologic upstaging to muscle-invasive or metastatic tumors occurs in one third of highly selected patients with clinically superficial bladder cancer who have had radical cystectomy, half of whom have extravesical disease (disease outside the bladder). Survival is significantly decreased in this group of upstaged patients. It is known that anywhere from 10-40 percent of patients will have immediate residual tumor at re-resection and progression to T2 (muscle invasive) happens in 10-50 percent. There is the perceived notion that if you detect someone once they become T2, you catch it early and offer surgery to improve survival. This is not necessarily true, as we have studies that have shown that those patients with T1 disease that becomes T2 behaves just as bad as any other muscle invasive cancer. Patients with the following characteristics are considered as having features indicative of disease that should be considered for early cystectomy – multifocal disease, bad location (inaccessible), T1 after BCG, evidence of lymphovascular invasion (LVI), and T1 without muscle in specimen.

MUSCLE INVASIVE TUMORS

Surgical treatment with radical cystectomy is still the most effective local therapy in muscle-invasive bladder cancer. Tumors that are organ-confined (T2) have a better prognosis than those that have extended through the bladder wall to the perivesical fat (T3) and beyond. If no neoadjuvant chemotherapy is given,

postoperative adjuvant chemotherapy is considered based on pathologic risk, such as positive nodes and pathologic T3 lesions.

For patients with superficial muscle-invasive T2 disease without hydronephrosis, bladder-sparing treatment with chemotherapy and radiation therapy may be possible after complete TURBT but the outcomes are not as optimal as open surgery. Outcomes from bladder sparing protocols including Shipley’s data from Mass General have reported: 5 and 10 year overall survival of 55% and 35%, respectively, and Disease specific survival of 65% and 60%, with over 30% of patients ultimately requiring cystectomy.

In patients with extensive comorbid disease or poor performance status making them imoperable, chemotherapy alone, radiation therapy, or TURBT may be suitable.

SURGICAL APPROACH

The appropriate surgical procedure involves a cystoprostatectomy in men (removal of bladder and prostate) and, in women, a cystectomy and usually a hysterectomy (removal of uterus and fallopian tubes/ovaries), followed by the formation of a urinary diversion. Forms of urinary diversion include an ileal conduit, continent cutaneous and orthotopic diversion. Relative contraindications to orthotopic diversion include CIS in the prostatic urethra or positive urethral margin. Orthotopic diversion or a neobladder provides bladder function similar to that of a native bladder with some increased risk for nighttime incontinence or urinary retention requiring intermittent self-catheterization. If the patient is interested in sexual preservation, a nerve sparing approach may be pursued as long as oncological safety is not compromised. Options for surgery include traditional open surgery or minimally invasive options of robotic assisted laparoscopic surgery. In my opinion, there are no clear advantages of robotics over open other than less chance of blood loss. For patients that are interested in nerve sparing and orthotopic reconstruction, the robotic approach does allow for more delicate dissection fo the nerves and potentially the structures critical for regaining of urine control. Hospital stay and post-operative complications seem to be equal. Although we are able to perform an adequate extended lymph node dissection, long term oncological outcomes are still being evaluated.

It is speculated that an extended lymph node dissection (in both lymph node positive and negative patients) may relate to the removal of undetected, lymph node micrometastases, and thus may improve survival in patients undergoing cystectomy. There is a growing body of evidence suggesting that the greater number of lymph nodes removed at the time of cystectomy for all patients is beneficial and that an extended lymph node dissection will remove a greater number of lymph nodes. The rational for an extended lymphadenectomy in high grade, invasive bladder cancer is based on the natural history of the disease process. Local invasion of bladder cancer can occur by either en bloc, lateral, or tentacular spread. The tumor progressively grows from its superficial origin in the mucosa to the muscularis propira, onto the periveiscal fat and contiguous organs. At each site, tumor cells have access to blood vessels and lymphatics through which they may metastasize to regional lymph nodes or distant sites. Therefore, I do promote an aggressive lymph node dissection, unless there is significant atherosclerotic disease or prior radiation.

NEOADJUVANT CHEMOTHERAPY

Increasing data support the role of neoadjuvant chemotherapy before cystectomy for T2 and T3 lesions. Two randomized trials show a survival benefit, particularly in patients with clinical T3 disease (palpable mass or unequivocal mass on CT). After 3 cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), the United States study showed no apparent increase in postoperative morbidity orMortality. Survival advantage are reported to be 5-11%. My philosophy is that neoadjuvant chemothearpy should be offered to all T2 and T3 patients with the understanding that this process may take up to 2-3 months with the potential for the following side effects: nausea, vomiting, chance for suppression of immune system, infections, and cardiac toxicity. All patients with muscle invasive disease should also see a medical oncologist prior to surgery to discuss the details of chemotherapy whether to be given before or after surgery.

Side effects of surgery: 30% of patients will have some form of complication after surgery whether the operation is done open or minimally invasive. Gastrointestinal complications are the major source of early morbidity after primary and salvage cystectomy and usually cause a slow return of bowel activity. This may require a temporary tube that goes from the nose into the stomach to suck back any bowel fluid that may be backing up and causing abdominal distention. Other side effects include bleeding, transfusion, infections, urinary tract injury, nerve injury, fistula, positive margins, incontinence, impotence, and even anesthetic complications such as heart attack and arrhythmia.

TYPES OF DIVERSION

ILEAL CONDUIT

Ileal Conduit is the simplest and oldest way to create a new bladder using the patient’s own small intestine. The ureters are plugged into a short segment of bowel and urine flows continuously into a bag attached to the skin. This type of diversion is usually reserved for older patients who do not have the dexterity to be able to pass a catheter into their neobladder or they have many additional medical conditions that put them at risk for complications with additional anesthetic time and surgery. The advantages of this type of diversion are the faster operative time and potentially easier recovery with least risk of complications. Its disadvantages include the fact that about one-fourth of patients can develop a hernia along side the diversion, the requirement of a bag and associated impact on body image. Urine around the stoma (opening) can sometimes also cause some local skin irritation. There is some controversy about the issue with urine backing up with this type of diversion to the kidneys, leading to possible stones and infections over time and potentially causing kidney damage.

CONTINENT CUTANEOUS

A continent cutaneous diversion also known as an Indian pouch or Right colon pouch involves the use of both large and small intestine to create a continent bladder that the patient empties themselves approximately 4 times a day by passing a catheter into a small hole in their abdomen. A one way valve mechanism is created so that urine is kept inside the reservoir (pouch) and will not leak out to the skin. The mechanism that allows for complete control of urine is the patient’s own appendix or ileocecal valve. The stoma or hole is smaller than a dime and looks like a duplicate belly button on the right side of the abdomen. Most patients keep a small bandage over the stoma. The advantages of this type of diversion are: better body image as the stoma is very discrete, no need for an external bag, no urine odor on the body, and high rates of urine control. The drawbacks of this type of diversion are that it involves more steps in the process of the operation. In addition, there is a higher risk of reoperation for complications with this type of diversion.

ORTHOTOPIC BLADDER OR NEOBLADDER

An orthotopic bladder or neobladder is a continent type of bladder made of the patient’s own small intestine attached back to the urethra for “normal” urination. This type of diversion is the most attractive to patients as it is he closest to their normal pre-operative voiding and does not require an additional stoma to evacuate the urine contents. It may take a patient up to 12-18 months before they regain their continence with this type of diversion. In order to be considered for this sort of reservoir (pouch) there must be no evidence of cancer at the urethra at the time of surgery, and patients must be willing and able to pass a catheter into the urethra to empty the reservoir (pouch) if necessary. The drawbacks of this include higher rate of leakage as compared to a cutaneous type of diversion and the fact that continence may not be achieved immediately. In addition, most reports of this type of diversion in women show almost 60% rates of hypercontinence (requiring the patient to catheterize from the vagina to empty their bladder) or incontinence (requiring either long term diapers or additional procedures to correct the incontinence). As a result, orthotopic diversions are seldom recommended in females.