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Chou R, Selph S, Buckley D, et al. Treatment of Nonmetastatic Muscle-Invasive Bladder Cancer [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2015 Jun. (Comparative Effectiveness Reviews, No. 152.)

Cover of Treatment of Nonmetastatic Muscle-Invasive Bladder Cancer

Treatment of Nonmetastatic Muscle-Invasive Bladder Cancer [Internet].

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Introduction

Background

Nature and Burden of Nonmetastatic Muscle-Invasive Bladder Cancer

Bladder cancer is the fourth most commonly diagnosed cancer in men and tenth most commonly diagnosed cancer in women in the United States.1 The American Cancer Society estimates there will be 74,690 new cases of bladder cancer in the United States in 2014 (about 56,390 men and 18,300 women), and about 15,580 deaths due to bladder cancer (about 11,170 men and 4,410 women).1

The lifetime probability of developing bladder cancer in the United States is approximately 3.8 percent in men and 1.2 percent in women, although the incidence of bladder cancer is increasing in women. Bladder cancer occurs primarily in men older than 60 and roughly twice as frequently in white compared with black men,2 though the number of deaths due to bladder cancer is similar, presumably due to delayed diagnosis in black men.

Bladder cancer remains an important health problem, with no improvement in associated mortality since 1975.3 Economic analyses have shown bladder cancer to be the costliest cancer to treat in the United States on a per capita basis, taking into account diagnostic testing, management, and long term followup.4 The most common risk factor for bladder cancer is smoking, though other risk factors include occupational exposures and family history. The most common symptom of bladder cancer is painless hematuria (blood in the urine).

Bladder cancer is staged based on the extent of penetration or invasion into the bladder wall and adjacent structures (Table 1).5 Bladder cancers that have not invaded the bladder smooth muscle layer (stage classifications Tis, Ta, and T1) are grouped as non-muscle-invasive bladder cancers. Stage classification T2 cancers are muscle-invasive, and higher stage cancers invade beyond the muscle layer into surrounding fat (stage classification T3 bladder cancer). Stage T4a cancers, which involve the prostate, vaginal wall, or uterus, are still considered localized because the bladder is contiguous with these structures. Stage T4b cancer, in which the tumor has spread to the pelvis or abdominal wall, bladder cancer involving the lymph nodes (N>0), and metastatic bladder cancer (M1) are considered nonlocalized and are outside the scope of this review. Approximately 25 percent of newly diagnosed bladder cancers present as stage 2 or higher tumors.6 Once bladder cancer invades muscle, it can quickly progress and metastasize, and is associated with a poor prognosis.

Table 1. Bladder cancer tumor staging.

Table 1

Bladder cancer tumor staging.

Interventions and Outcomes for Muscle-Invasive Bladder Cancer

Once bladder cancer has been diagnosed, a number of factors affect prognosis and treatment options. These include the stage of the cancer, tumor grade, whether the tumor is an initial tumor or a recurrence, the patient’s age and general health, and other factors. A variety of molecular and other biomarkers, including p53, mTOR pathway genes, pRb, MRE11, BRCA1, ERCC1, MDR1, ET-1, and others, have also been evaluated for their prognostic value and to potentially inform selection of treatments.10

For nonmetastatic muscle-invasive bladder cancer, the gold standard treatment option is radical cystectomy combined with neoadjuvant (administered prior to chemotherapy) systemic chemotherapy with a cisplatin-based regimen (methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC], cisplatin, methotrexate, and vinblastine [CMV], or gemcitabine and cisplatin).11 The components of these treatment regimens are US Food and Drug Administration approved and clinically available in the United States, though the combinations do not have a specific bladder cancer indication. Other chemotherapy regimens and adjuvant (administered after cystectomy) systemic chemotherapy have also been evaluated. Selection of therapy is complicated by the fact that patients with bladder cancer are often older and have multiple medical comorbidities. Therefore, factors such as performance status and renal function must be considered in relation to treatment effectiveness and adverse effects. For example, medically frail patients with baseline renal insufficiency may not be ideal candidates for cisplatin-based therapy because of potential renal toxicity; an alternative chemotherapeutic regimen with potentially less renal toxicity is gemcitabine and carboplatin.

Regional lymph node dissection in conjunction with cystectomy or partial cystectomy is recommended because it can diagnose clinically nonevident lymph node metastases and may be associated with improved cancer-specific survival, but may be underutilized.11-14 Similarly, cystectomy appears to be underused for non-metastatic muscle-invasive bladder cancer relative to recommendations from clinical practice guidelines,15 in part because removal of the urinary bladder necessitates reconstruction with a urinary diversion, and there is interest in bladder-sparing options that combine maximal transurethral resection of bladder tumor (TURBT), chemotherapy, and/or radiation therapy. Maximal TURBT refers to a procedure involving resection of all visible tumors into deep muscle or perivesical fat, with at least 1 cm resected margin of normal mucosa.16 Several modalities of radiation therapy have been evaluated, including external beam radiation therapy and interstitial radiation therapy (brachytherapy). These alternative treatments are generally only recommended for carefully selected, well-informed patients due to the need for continued surveillance and invasive diagnostic procedures, and the risk of eventual cystectomy.11 The comparative effectiveness of these treatments or their combinations is an important clinical issue.

Rationale for Evidence Review

Systematic reviews on the comparative effectiveness of treatment options for muscle-invasive bladder cancer have primarily focused on the effectiveness of neoadjuvant and adjuvant chemotherapy in patients undergoing radical cystectomy. A systematic review that also evaluates the effectiveness of bladder-preserving therapies, the effectiveness of regional lymph node dissection, and includes recently published evidence focusing on treatments used in current practice may be useful for developing updated clinical guideline for muscle-invasive bladder cancer.

Scope of Review and Key Questions

This topic was nominated for review by the American Urological Association and focuses on treatment of nonmetastatic muscle-invasive bladder cancer. The Key Questions and analytic framework used to guide this report are shown below. The analytic framework (Figure 1) shows the scope of this review, including the target population, interventions, and health outcomes we examined.

Figure 1 is an analytic framework that depicts the populations, interventions, outcomes, and adverse effects of interest for treatment of non-metastatic muscle-invasive bladder cancer. The far left of the framework describes the target population for treatment as patients with non-metastatic muscle-invasive bladder cancer, stage T2, T3, or T4a; N0; M0. To the right of the populations is an arrow to represent the treatments for muscle invasive bladder cancer, including bladder-preserving chemotherapy and/or radiation therapy, partial cystectomy, regional lymph node dissection, and neo-adjuvant or adjuvant chemotherapy. Below the treatments is an oval for the adverse effects of these treatments. To the right of the treatments are health outcomes of interest, including mortality, recurrence of cancer, progression or metastasis of cancer, quality of life and functional status.

Figure 1

Analytic framework. a Questions on diagnostic testing and identification of patients with muscle-invasive bladder cancer are addressed in a complementary review of non-muscle-invasive bladder cancer. b Treatments include: bladder-preserving chemotherapy (more...)

Key Questions

Key Question 1. For patients with nonmetastatic muscle-invasive bladder cancer, what is the effectiveness of bladder-preserving treatments (chemotherapy, external beam or interstitial radiation therapy, partial cystectomy, and/or maximal transurethral resection of bladder tumor) for decreasing mortality or improving other outcomes (e.g., recurrence, metastasis, quality of life, functional status) compared with cystectomy alone or cystectomy in combination with chemotherapy?

  1. Does the comparative effectiveness differ according to tumor characteristics, such as histology, stage, grade, size, or molecular/genetic markers?
  2. Does the comparative effectiveness differ according to patient characteristics, such as age, sex, race/ethnicity, performance status, or medical comorbidities such as chronic kidney disease?
  3. What is the comparative effectiveness of various combinations of agents and/or radiation therapy used for bladder-preserving chemotherapy?
  4. What is the effectiveness of different bladder-preserving treatments (chemotherapy, external beam or interstitial radiation therapy, partial cystectomy, and/or maximal transurethral resection of bladder tumor) compared with one another?

Key Question 2. For patients with clinically non-metastatic muscle-invasive bladder cancer that is treated with cystectomy, does regional lymph node dissection improve outcomes compared with cystectomy alone?

  1. Does the comparative effectiveness differ according to tumor characteristics, such as histology, stage, grade, size, or molecular/genetic markers?
  2. Does the comparative effectiveness differ according to the extent of the regional lymph node dissection (e.g., as measured by the number of lymph nodes removed or the anatomic extent of dissection)?

Key Question 3. For patients with nonmetastatic muscle-invasive bladder cancer that is treated with cystectomy, does neoadjuvant or adjuvant chemotherapy improve outcomes compared with cystectomy alone?

  1. What is the comparative effectiveness of various combinations of agents used for neoadjuvant or adjuvant chemotherapy?
  2. Does the comparative effectiveness of various combinations of agents used for neoadjuvant or adjuvant chemotherapy differ according to tumor characteristics, such as histology, stage, grade, size, or molecular/genetic markers?
  3. Does the comparative effectiveness differ according to patient characteristics, such as age, sex, race/ethnicity, performance status, or medical comorbidities such as chronic kidney disease?
  4. Does the comparative effectiveness of neoadjuvant or adjuvant chemotherapy differ according to dosing frequency and/or the timing of its administration relative to cystectomy?

Key Question 4. What are the comparative adverse effects of treatments for nonmetastatic muscle-invasive bladder cancer?

  1. How do adverse effects of treatment vary by patient characteristics, such as age, sex, race/ethnicity, performance status, or medical comorbidities such as chronic kidney disease?

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