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Contemporary Management of Locally Invasive Bladder Cancer

Contemporary Management of Locally Invasive Bladder Cancer

ABSTRACT: Bladder cancer is a heterogeneous disease that carries a significant risk of progression and lethality. Radical cystectomy with pelvic lymph node dissection remains the predominant treatment for patients with muscle-invasive disease and offers the best chance of long-term disease control. However, radical surgery is insufficient in patients with advanced-stage disease. Current staging techniques are limited in their ability to detect extravesical disease and lymph node metastases. Thus, integration of systemic therapy with surgery to potentially eradicate micrometastases provides survival superior to that with surgery alone. Yet, because bladder cancer is typically a disease that affects an elderly population of patients with multiple comorbidities, there is a need for less invasive and bladder-conserving therapies. Some physicians have attempted to minimize morbidity by pursuing minimally invasive surgical techniques; however, the long-term effectiveness of this approach remains unproven. Trimodality therapy could be considered in patients with favorable disease status, and may be offered as a reasonable alternative, but does not replace standard treatments for patients with more aggressive disease. Consequently, further improvements in outcomes will rely on improved patient selection based on clinical and molecular assessments.

Introduction

Bladder cancer remains the fourth most common cancer in men and consistently falls within the top 10 most common cancers in women.[1] Additionally, in the United States, it is one of the most expensive cancers to treat, costing the government an estimated $3.7 billion per year, mainly because of the rigorous follow-up needed to detect recurrent disease.[2] Initially, the majority of patients are diagnosed with localized disease (20% of which is muscle-invasive), with only 8% and 4% of patients having locally advanced and metastatic disease, respectively.[1] Radical surgery is the predominant treatment for those who present with de novo muscle-invasive bladder cancer (MIBC) and those with non–muscle-invasive disease that progresses after intravesical therapy. However, because bladder cancer typically affects an elderly population (with a median age of 73 years at diagnosis[3]), there is a need for less invasive and bladder-conserving therapies.

Radical Surgery

Radical cystectomy (RC) involves removal of the bladder and seminal vesicles en bloc in males, and removal of the bladder, uterus, fallopian tubes, ovaries, and a segment of the anterior vaginal wall in females. Bowel is commonly utilized for reconstructive purposes to store and empty the urine. RC typically involves an operation lasting between 4 and 10 hours and a hospital stay ranging between 5 and 10 days. Postoperative complications are common and include atelectasis, wound infection, and ileus, plus the complications of prolonged anesthesia that occur in an elderly population, most of whom have pre-existing coronary and pulmonary disease.

Current surgical techniques have been in evolution for the last 40 years. Early results indicated that only about 50% of patients were cured with surgery, and most patients died of metastatic disease within 3 years of diagnosis. During the 1970s, various preoperative radiation regimens were employed, but these failed to show convincing evidence of benefit. The main limitation of RC was the considerable associated morbidity. However, surgical techniques have significantly improved over time, and the procedure has become much more accepted, particularly since the implementation of orthotopic urinary diversions (ie, neobladders).

Now RC with pelvic lymph node dissection is considered the gold standard of treatment for MIBC and offers the best chance of long-term disease control. However, survival is closely associated with pathologic stage, and unfortunately, clinical staging diverges from pathologic staging in around 50% of cases.[4] Consequently, there is obviously a great need for better determinants of stage. Molecular markers are in the forefront of research in this area, with many groups trying to identify gene signatures for each pathologic feature.[5]

Lymph node dissection

A well-performed lymphadenectomy is an essential component of RC. Not only is the removal of lymph nodes prognostic, as in most other cancers, but the extent of dissection has an impact on outcome.[6,7] A “standard” lymph node dissection involves removal of all tissue within the boundaries of the genitofemoral nerve laterally, the bladder medially, the circumflex iliac vein inferiorly (lymph node of Cloquet), the bifurcation of the common iliac artery superiorly, and hypogastric vessels posteriorly. Lymph node packets are typically removed from regions around the external iliac, internal iliac, and obturator vessels, but recent mapping studies have more accurately described the common landing zones for nodal metastases.[8] An “extended” lymph node dissection is carried up to the aortic bifurcation and includes presacral nodes. There is no exact consensus on the minimum number of lymph nodes that must be removed for success, but early reports suggested that at least nine would ensure adequate information for proper staging.[9] Most urologists would agree that the removal of more nodal tissue results in more accurate staging and removal of undetected micrometastases. Thus, there is growing evidence that an extended dissection may provide a clinically meaningful benefit by conferring a survival advantage in both node-positive and node-negative patients.[10,11] A randomized trial of “standard” vs “extended” lymph node dissection is currently enrolling patients, and its results will be crucial in expanding our understanding of this key question.

The concept of lymph node density (ie, the number of positive nodes as a percentage of total nodes removed) reflects the quality of the nodal dissection and tumor burden.[12] Lymph node density has been confirmed as a useful tool in predicting survival,[13,14] and data suggest that lymph node density performs better than the N status of TNM staging in risk stratification. Recently, the relevance of lymph node metastases and the benefits of lymphadenectomy have been nicely summarized in a collaborative review concluding that an “extended” lymph node dissection can be curative in patients with metastases or micrometastases and thus should be offered to all patients undergoing curative radical surgery.[8]

Urinary diversion

Diversion of urine after removal of the bladder is a permanent quality-of-life issue after surgery. Today, there are three main categories of urinary diversion: a noncontinent cutaneous diversion (most commonly the ileal conduit), continent cutaneous diversions, and orthotopic reservoirs attached to native urethra (ie, neobladders).

An ileal conduit represents the simplest type of diversion and is associated with the fewest intraoperative and immediate postoperative complications. However, there are several prevalent associated long-term complications, including stomal stenosis, chronic or recurrent pyelonephritis, calculus disease, ureteroenteric anastomotic strictures, and renal deterioration. With regard to continent cutaneous diversions, the major long-term problem remains the provision of a durable continence mechanism.

Orthotopic neobladders have become more popular because they offer a number of theoretical advantages, including the ability to most nearly recreate normal voiding function, the ability to achieve continence with use of the native rhabdosphincter, avoidance of an abdominal stoma, easier urethral surveillance, a potentially lower urethral recurrence rate, and a superior body image.[15,16] However, there are risks of urinary incontinence, particularly nocturnal enuresis, of hypercontinence, and potentially of the need to catheterize and irrigate a pouch to drain excess mucus.

Various factors are important in the selection of patients for each type of diversion. To minimize the risk of urethral recurrence, investigators have found that patients undergoing orthotopic neobladder should not have bladder neck involvement, prostatic stromal invasion, or positive surgical margins on frozen section analysis.[17] Additional considerations include patient preference and ability, mobility, manual dexterity, renal dysfunction, mentation, bowel availability, comorbidities, and life expectancy.

Disease recurrence rates are independent of urinary diversion type. Approximately 5% to 7% of men and 1% to 4% of women develop a urethral recurrence after the creation of an orthotopic neobladder.[18-20] Daytime continence rates remain greater than 95% for men and 90% for women, with nocturnal continence rates as high as 75% in men and 57% in women.[21,22] Some believe that an orthotopic neobladder improves quality of life compared with an ileal conduit, but most retrospective studies report no significant measurable difference.[23]

Recently, investigators evaluated the utilization of ileal conduits and orthotopic neobladders in a large series of patients. They found a significant trend toward the use of ileal conduit urinary diversion in female patients, patients of advanced age, those with significant medical comorbidities, and those with locally advanced disease. However, orthotopic neobladders continue to be the most common urinary diversion in patients younger than 65 years.[24]

Complications

RC remains one of the most challenging and complex surgeries in the urologic arsenal, for both the surgeon and the patient. Although operative mortality is low at 1%, overall complications are common, with an incidence near 40%.[25] Early complications include pulmonary (atelectasis, pneumonia, pulmonary embolus, etc), gastrointestinal (ileus, small bowel obstruction, enterocutaneous fistula, etc), anastomotic (urine leak or obstruction), hemorrhagic, and wound-related effects (infection, dehiscence, and evisceration). Late complications include anastomotic site-related effects (strictures, stones, reflux), ostomy-related effects (hernias, prolapse), infections (pyelonephritis), and metabolic effects (acid/base disturbances, electrolyte disturbances, vitamin B12 deficiency).[26]

Quality of care and the ability to control and improve outcomes continue to be important issues. We know that postoperative mortality after RC is inversely associated with the number of procedures performed. Many studies have suggested that high-volume providers have better infrastructure and more experience, which can lead to better outcomes. Volume is seen as a proxy for high quality of care; thus, centralization is believed to improve outcomes for patients undergoing RC. A recent meta-analysis confirmed this volume-outcome relationship. In particular, positive associations are seen between high-volume hospitals (and high-volume surgeons) and both mortality and survival.[27] Furthermore, application of a fast-track clinical care pathway for patients undergoing RC reduces morbidity and improves recovery.[28]

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