Bladder Cancer Muscle Invasive & Metastatic

Clinical Presentation, Diagnosis & Evaluation:

• Significant progress has been made in the management of invasive cancer, and, along with our increased knowledge of multimodal therapy, a multidisciplinary approach to the evaluation and management has become increasingly imperative.
• The urologist, medical oncologist, and radiation oncologist play a central role in integrating the disciplines of surgery, chemotherapy, and radiation therapy in order to achieve the goal of long-term cancer control.

Natural History - Bladder Cancer towards Muscle Invasive and Metastatic:

• The majority (80%) of patients with bladder cancer present de novo with muscle-invasive disease as its first manifestation.
• The remaining 15% to 20% progress from non–muscle-invasive cancer after treatment with intravesical therapy. 
• Deaths due to bladder cancer invariably occur as a result of distant metastases present at the time of loco-regional therapy. 
• Progression of cancer after definitive loco-regional therapy commonly occurs within the first 2 years after treatment. 
• Late recurrences are more common after perioperative systemic chemotherapy and often occur in unusual sites including the central nervous system, bowel serosa, and peritoneum. 
• Muscle-invasive bladder cancer must be considered as a systemic disease and therapeutic strategies must be designed around the integration of treatment targeting the loco-regional disease (bladder and pelvic lymph nodes) and occult visceral metastatic disease according to pathologic risk factors.

Histology

• Primary cancers of the bladder arise from the urothelium, and by far the most common cell type is transitional cell. 
• Squamous cell predominates in Middle Eastern countries where bilharziasis is endemic. 
• It occurs more frequently in Western countries in women and in the setting of chronic indwelling catheters and recurrent infection. 
• As the prevalence of bilharziasis has diminished significantly, transitional cell carcinoma (TCC) now accounts for more than one half of bladder cancer diagnosed in Egypt. 
• Adenocarcinomas of the bladder are uncommon but occur in the bladder base/trigone area. 
• Patients with exstrophy are at increased risk. 
• Surgical treatment of urachal adenocarcinoma is partial cystectomy, and the biology is similar to that of colorectal adenocarcinoma. 
• Small cell neuroendocrine cancer is also a rare variant and may be the predominant histology or may be mixed with TCC. 
• This phenotype is easily distinguished by immunohistochemistry expressing synaptophysin and chromogranin. 
• Treatment requires neoadjuvant chemotherapy (cisplatin and etoposide) followed by radical cystectomy or radiation therapy. 
• Small cell tumors may also be associated with paraneoplastic syndromes including ectopic adrenocorticotropic hormone (ACTH) production, hypercalcemia, and hypophosphatemia. 
• Other neuroendocrine tumors occur in the bladder and include carcinoid tumors, which may originate in the bladder or invade the bladder from the gastrointestinal tract, most commonly from the appendix. 
• Large cell neuroendocrine tumors are rare with few cases reported in the literature and are believed to behave in a manner similar to that of small cell tumors.
• Other unusual variants reported have included lymphoepithelioma-like cancers, which have a better prognosis than high-grade invasive TCCs, although treatment is similar stage for stage. 
• The micropapillary variant resembles ovarian papillary serous cancer and is aggressive. It tends toward high grade and high stage and is frequently associated with lymphatic and vascular invasion. 
• Radical cystectomy is the treatment of choice because this phenotype typically does not respond to chemotherapy directed at TCC. 
• Rhabdomyosarcoma is seen in both children and adults, and leiomyosarcoma is seen in adults. 
• Primary lymphoma of the bladder is rare, but the bladder may be involved in up to 10% of cases of systemic lymphoma.

Staging Evaluation: Regional and Metastatic Disease

• Laboratory tests and radiographic imaging are directed at determining the effect of the local tumor on the upper urinary tract and the presence or absence of synchronous urothelial cancer of the ureter, renal pelvis, or urethra, and for evaluating the status of potential sites of metastatic disease. 
• Laboratory testing at a minimum should include blood urea nitrogen (BUN), creatinine, electrolytes, complete blood count, and liver function tests. Imaging studies are directed to the most common sites of visceral metastasis, which include lung, liver, and bone. 
• Following chemotherapy, metastasis may occur in unusual sites including the central nervous system and the peritoneum (with late presentation of bowel obstruction), but these sites are generally not a focus of staging at initial presentation.
• Computed tomography (CT) has largely replaced intravenous urography for upper tract imaging. CT provides the added benefit of cross-sectional imaging of the pelvic, iliac, and retroperitoneal lymph nodes, as well as the liver. 
• Histologic confirmation of metastatic disease is desirable because its presence has a significant effect on treatment decisions and evaluating response to subsequent therapy. 
• A chest radiograph is important for evaluating the lungs and mediastinum. 
• A chest CT is obtained to further define abnormalities and should be obtained routinely in patients with muscle-invasive disease or N+ disease in whom the risk of visceral metastasis is greatest. 
• Bone scintigraphy is obtained in these highest-risk patients and in patients with an elevated alkaline phosphatase or new-onset bone pain. 
• An MRI may be useful for patients with an allergy to iodinated contrast or to resolve questions about an equivocal bone scan. The introduction of novel contrast agents with MRI may provide a more sensitive means for detecting nodal metastases.
• Positron emission tomography (PET) is used increasingly in oncology. 
• Combination with CT is now standard and thus provides more accurate localization of abnormalities. 
• Although there is as yet no defined role for routine staging of nodal or visceral metastases in invasive bladder cancer, PET/CT can be particularly helpful in discerning nodal or visceral metastatic disease when these findings will determine the use of chemotherapy or surgery.

Radical Cystectomy and Bilateral Pelvic and Iliac Lymphadenectomy

• Radical cystectomy provides excellent local control of the primary tumor and should include the bladder and surrounding perivesical soft tissue, prostate, and seminal vesicles in men and the ovaries, uterus/cervix, and anterior vagina in women. In sexually active women, vaginal preservation and/or reconstruction must be discussed and planned preoperatively.
• Involvement of the urethra or bladder neck is an absolute contraindication to sparing the urethra in women, and a posterior-based invasive cancer is a relative contraindication.
• Lymph node (LN) metastasis is found in 20% to 25% of patients who undergo radical cystectomy (RC) and pelvic lymphadenectomy for bladder cancer, and it is the most important prognostic factor in these patients, predicting significantly decreased recurrence-free survival and overall survival compared with that for patients without nodal metastases.

Staging

• The current TNM staging system distinguishes between number of nodes with metastases, the size of nodal metastases, and the anatomic location, with nodal metastasis above the common iliac bifurcation denoting M1 disease and thus equivalence to visceral metastasis. 
• The seventh edition of the American Joint Committee on Cancer (AJCC) Staging Manual (released October 2009) notes that at least 12 nodes should be removed. See Staging

Outcomes Associated with Nodal Status

• With so many factors contributing to the variability in node counts, one could argue that the anatomic extent and completeness of the node dissection deserve the most emphasis. It is clear that the more tissue removed, the more nodes a diligent pathologist will identify, and this should increase sensitivity in detecting nodal metastases.

Survival and Treated Natural History 

• Pathologic tumor stage and nodal status are the primary variables affecting the risk of progression and survival probability following cystectomy.
• Positive surgical margins have an adverse impact on outcome.
• Recent studies suggest that improved outcomes are associated with high-volume surgeons and hospitals and that patient's age and body mass index (BMI) may also affect morbidity and survival.
• Up to 50% of patients with infiltrating disease develop metastases and ultimately succumb to their disease. Failure is usually due to occult metastatic disease present at the time of initial diagnosis. Long-term survival remains low and chemotherapy currently provides the potential for cure only in selected patient. 
• After metastases develop, there are few long-term survivors, although some 70% of patients have disease that is sensitive to chemotherapy. 
• The suggestion is that systemic treatment in addition to radical cystectomy is required. Extensive lymph node dissection has both prognostic and therapeutic significance, and effective systemic therapies that eliminate micrometastases may improve outcome.
• Perioperative chemotherapy is administered before (neoadjuvant) or after (adjuvant) cystectomy (bimodality therapy) to eradicate subclinical disease and primarily to improve survival. 
• Concomitant chemotherapy and radiation therapy with thorough transurethral resection of the bladder (TURB) (trimodality therapy) is another method of treating patients with invasive bladder cancer and is particularly aimed at bladder preservation.

Neoadjuvant Chemotherapy

• Neoadjuvant chemotherapy has been used for patients with operable clinical stage T2 to T4a muscle-invasive disease. The rationale for chemotherapy before cystectomy or, in some cases, full-dose radiation therapy (RT), is based on the intent to treat micrometastatic disease present at diagnosis. 

• Chemotherapy before surgery has several advantages.

• Therapy is better tolerated before surgery or radiation. 
• Chemotherapy-related toxicities are considerably less in patients with localized disease than in those with metastatic disease on the basis of performance status. 
• Patients are often able to tolerate a greater dose intensity and more cycles of chemotherapy preoperatively than postoperatively. 
• Neoadjuvant chemotherapy allows in vivo drug sensitivity testing that may provide useful information for later therapy. 
• The primary tumor can be evaluated for response, which also has major prognostic significance. 
• Preoperative chemotherapy may down-stage tumors, potentially allowing for technically easier surgery.
• The major disadvantage of neoadjuvant chemotherapy is a delay in definitive local therapy in patients who do not respond or whose disease progresses. 
• An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy has even been associated with a poorer outcome.

Adjuvant Chemotherapy

• In patients with pT3-4 and/or N+M0 disease, 5-year survival after radical cystectomy is only 25% to 35% .
• As a result, adjuvant chemotherapy has been advocated for high-risk patients in an effort to delay recurrence and prolong survival. 
• Delivery of chemotherapy postoperatively has potential advantages. 
• An adjuvant approach allows selection of patients at highest risk of metastatic or recurrent disease on the basis of an accurate pathologic evaluation.

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