Bladder Cancer

Cancers of the Bladder, Urethra, and Penis

Author: Daniel Petrylak, MD (More Info)
Section Editor: Brian Rini, MD, FACP
Editor in Chief: Ramaswamy Govindan, MD
Last Reviewed: 7/21/15 (What's New)

Introduction and Epidemiology
Summary

Bladder cancer

Is among the most common malignancies
Annual incidence of approximately 35.8 cases per 100,000 males per year; 9 cases per 100,000 females[SEER 2015]
Median age at presentation is 60-65 years
Increased incidence in the Great Lakes region of the United States, the Mediterranean basin, and regions with an increased incidence of schistosomiasis

Most common associations are cigarette smoking and exposure to dyes, industrial solvents, exhaust fumes, reduced intake of fluids, and analgesic abuse[Raghavan 1990; Fleshner 2004]

Pathology

Bladder cancer can occur anywhere along the urothelial tract
May occur just at 1 site or may be multifocal
Approximately 90% of incident cases are urothelial carcinoma, with approximately 5% to 10% being squamous cell carcinoma, 4% to 5% adenocarcinoma, and the remainder consisting of rare cancers
Bladder cancer appears to originate from a solid-tumor stem cell,[Brown 1990] which has the ability to differentiate into different histologic patterns
Noninvasive papillary carcinoma is the single most common presentation for bladder cancer and represents more than 60% of cases

Molecular Biology and Biomarkers

Alterations in chromosomes 9, 11, and 17 with allelic loss and loss of heterozygosity are the most common defects in bladder cancer
Loss of function of PTEN and RB are also implicated in progression[Puzio-Kuter 2009; Castillo-Martin 2010]
Tumor angiogenesis is an independent prognostic indicator
ESM1, thrombospondin 1, and basic fibroblast growth factor are angiogenesis-associated markers and independent predictors of disease recurrence and cancer-specific mortality[Shariat 2010; Roudnicky 2013]
Epigenetic alterations such as DNA methylation play an important role in urothelial carcinoma
Genomewide expression arrays and proteomics are important tools for diagnosis, staging, and tumor characterization[Mitra 2006b; Hussain 2013; Pilchowski 2011]
Several potential therapeutic targets have been reported by the Cancer Genome Atlas Research Network, including[Weinstein 2014]:
HER2
ERBB3
FGFR3
PI3K/AKT/mTOR
CDKN2A/CDK4/CCND1
RTK/RAS

Clinical Features, Staging, and Prognosis
Clinical Features

Patients with noninvasive and invasive tumors commonly present with asymptomatic hematuria (diagnosed on urinalysis), visible hematuria, and/or urinary frequency, dysuria, burning, or nocturia
More advanced invasive tumors may also be associated with slowing of urinary stream, pelvic pain, dyspareunia, and rarely pneumaturia or fecal incontinence
Common sites of metastasis include distant lymph nodes, lung, liver, and bone, and less commonly, brain or skin
Symptomatic manifestation of metastasis is typically based on the site of involvement
The most common nonmetastatic manifestation of malignancy is the development of thrombosis

Diagnosis and Staging

Initial and diagnostic assessment may involve urinalysis, urinary cytology and/or cystoscopic examination,[NCCN Bladder Cancer] biomarker dipstick assays, molecular analysis, as well as assessment of possible infection
Molecular analysis can detect aneuploidy changes in chromosomes 3, 7, and 17 associated with high-grade tumors and loss of the 9p21 site characteristic of low-grade disease[Ikemoto 2004]
NCCN recommends that pelvic CT should be considered before transurethral resection of bladder tumor for patients with sessile or high-grade tumors (Management Guidelines) (C)[NCCN Bladder Cancer]
The most widely applied classification of staging is the conjoint model of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer (Table 1)[Edge 2010]
Transurethral resection of bladder tumor may provide eradication of tumor and accurate staging of noninvasive disease

Prognosis

The prognosis of bladder cancer largely reflected by the following factors: stage and grade of the tumor, multifocality, presence of lymphovascular invasion, association with carcinoma in situ, morphology, pattern of gene mutation, presence of anemia, and hydronephrosis
The American Joint Committee on Cancer Staging Classification generally correlates well with outcome (Table 1)[Edge 2010]
The identification of specific prognostic biomarkers is ongoing[Tian 2013; Foutadakis 2013]
Data suggest that increased expression of either CHD1L or BCL2L12 associated with decreased survival

Treatment by Tumor Type
Treatment of Noninvasive Bladder Cancer

Transurethral resection of bladder tumor is the hallmark of noninvasive bladder cancer treatment[Raghavan 1995; Nieder 2005]
Can be followed by postoperative use of intravesical therapy (immunologic or cytotoxic reagents) to reduce the risk of recurrence[Solsona 1999; Huncharek 2000; Dalbagni 2006; NCCN Bladder Cancer]
Multiple random biopsies of apparently normal urothelium should be performed to identify occult carcinoma in situ if urine cytology is positive or in the presence of high-grade disease
Endoscopic resection should be repeated within 4-6 weeks of the initial resection in patients with high-grade disease and/or T1 tumors
The grade and stage of the tumor dictate subsequent clinical management
Noninvasive, low grade tumors are often given adjuvant intravesical therapy with Bacillus Calmette-Guérin (BCG)
Adverse effects of BCG include local or systemic infection, influenza-like syndrome, granuloma formation, and possibly life-threatening sepsis
After completing treatment, patients should be monitored closely with periodic cystoscopy, urine cytology, and/or tumor marker evaluation at 3- to 6-month intervals to detect recurrence

Treatment of Invasive Bladder Cancer

Radical cystectomy with bilateral pelvic lymphadenectomy is the standard treatment for clinically localized invasive bladder cancer[Raghavan 1995; Stein 2001; NCCN Bladder Cancer]
Radical cystectomy without adjuvant therapy is curative in up to 60% to 70% of patients with invasive T2 bladder cancer
5-year OS rate in patients with T2-T3 disease ranges from 40% to 65%
Laparoscopic radical cystectomy has been reported in small series from centers experienced in laparoscopic surgery[Haber 2007; Cheung 2013]
Drawbacks include technical difficulty, longer operating time, and possible limitations in oncological efficiency because of less-clear observation of nodes and pelvic structures for evidence of tumor involvement
Potential advantages include reduced blood loss, less postoperative pain, decreased time for bowel function return, and shorter convalescence
Use of pelvic lymph node dissection with radical cystectomy has both staging and therapeutic value
In the US, standard dissection is extremely limited—including only the digastric, internal iliac, and external iliac nodes
The greater the extent of lymph node dissection, whether the nodes are positive or negative, the better the outcome for patients.

Treatment Approaches
Role of Radiotherapy

For patients with invasive, clinically nonmetastatic bladder cancer who are not surgical candidates, radiation is the treatment of choice[Gospodarowicz 1989; Mameghan 1992; Borgaonkar 2002; Chung 2007]
Combination with systemic chemotherapy enhances radiation responsiveness[James 2012]
Favorable prognostic features include small, localized, T2 tumors; absence of hydronephrosis; normal renal function; and absence of anemia
Toxicities of radiation include cutaneous inflammation, proctitis, cystitis or bladder fibrosis, impotence, incontinence, and development of secondary malignancies in the areas adjacent to the radiation field
NCCN guidelines recommend chemoradiation therapy with an initial radiation dose of 40-45 Gy and total dose of 66 Gy (Management Guidelines) (C)[NCCN Bladder Cancer]

Neoadjuvant (Preemptive) Chemotherapy

Neoadjuvant systemic chemotherapy can cause remissions in primary bladder cancers and result in downstaging, with patients sometimes achieving a complete clinical and pathological remission[Raghavan 1995]
Neoadjuvant multidrug chemotherapy regimens have shown a survival benefit in patients with invasive bladder cancer (Table 2)
NCCN recommends neoadjuvant treatment with cisplatin-based combination chemotherapy for patients with invasive, T3 and T4 tumors and negative lymph nodes (Management Guidelines) (C)[NCCN Bladder Cancer]
No multidrug cytotoxic regimen has been shown to be superior, or even equivalent to, the MVAC and CMV regimens in this setting

Adjuvant Chemotherapy

No adequately powered trial has demonstrated an OS benefit of adjuvant chemotherapy administered after radical cystectomy for patients with high-risk, T3-T4 tumors and/or lymph node involvement [Skinner 1991; Freiha 1996; Stöckle 1992; Sternberg 2014]
Improvement in PFS demonstrated with immediate vs deferred chemotherapy[Sternberg 2014]
High expression levels of MDR1 and ERCC1 may predict inferior PFS in patients who received cisplatin-based adjuvant chemotherapy for locally advanced bladder cancer[Hoffmann 2010]
NCCN recommends adjuvant chemotherapy for carefully selected, otherwise healthy patients with high-risk disease proven at cystectomy (Management Guidelines) (C)[NCCN Bladder Cancer]

Combined Modality Strategies

The combination of radiation and chemotherapy associated with improved survival vs either treatment alone[Bamias 2013]
Particularly useful in patients with a T2 tumor, no hydronephrosis, and who have not undergone multiple transurethral resection of bladder tumor procedures
Chemoradiation failure with local progression or relapse, may increase the difficulty of salvage surgery because of the formation of dense adhesions

Metastatic Bladder Cancer
Chemotherapy

Chemotherapy is the treatment of choice for patients with metastatic bladder cancer
MVAC regimen:
Produces objective responses in > 60% of cases
Is superior to single-agent cisplatin and combination cyclophosphamide, doxorubicin, and cisplatin[Logothetis 1990]
Is associated with substantial toxicity including severe gastrointestinal effects, stomatitis, myelosuppression, and occasionally renal dysfunction and cardiac failure[Saxman 1997; Logothetis 1990]
Accelerated MVAC is well tolerated and results in similar pT0 rates as the standard 12-week MVAC regimen[Plimack 2014]
Single-agent response rates of approximately 20% to 30% have been reported for paclitaxel, gemcitabine, docetaxel, ifosfamide, and pemetrexed
The combination of these agents with other standard or investigational drugs has resulted in response rates of 50% to 80%, often with less toxicity than the MVAC regimen
Category 1 NCCN guidelines recommendations include (Management Guidelines) (C):
Dose-dense MVAC preferred over the standard MVAC chemotherapy regimen[NCCN Bladder Cancer]
Combination of gemcitabine and cisplatin as an alternative to dose-dense MVAC[NCCN Bladder Cancer]
Dose-dense MVAC and gemcitabine/cisplatin are significantly less toxic compared with standard MVAC[von der Maase 2000; Sternberg 2006]

Immunotherapy

The role of immune checkpoint inhibition (PD-1 pathway) as a therapeutic modality for metastatic urothelial cancer is being actively investigated[Powles 2014]
Clinical activity demonstrated with anti–PD-L1 antibody atezolizumab (MPDL3280A) with acceptable toxicity[Powles 2014; Petrylak 2015a]
Early data with pembrolizumab suggests agent is safe and active in heavily pretreated urothelial carcinoma[Plimack 2015]
Nivolumab as monotherapy or in combination with ipilimumab is in early phase trials

Targeted Therapy

HER2 amplification and/or overexpression is thought to influence prognosis in patients with bladder cancer,[Marin 2010] clinical development of HER2-targeted therapies in this setting continues[Martin 2014]
Maintenance therapy with lapatinib in patients with HER1/2-positive metastatic bladder cancer did not provide clinical benefit after chemotherapy[Powles 2015]
The MET pathway may play a role in the pathogenesis of urothelial carcinoma by promoting angiogenesis and tumor growth via the upregulation of VEGF
Cabozantinib inhibits the MET pathway and has also demonstrated clinical activity and manageable toxicity[Apolo 2014]
Ramucirumab in combination with docetaxel showed statistically significant improvement in PFS in second-line therapy for urothelial carcinoma[Petrylak 2015b]

Uncommon Cancers of the Bladder

Uncommon histology variants tend to be more resistant to chemotherapy than the pure urothelial carcinomas
Definitive surgical resection or radiotherapy may improve survival and should be considered
Prognostic factors associated with uncommon metastatic tumors include sites of involvement, growth characteristics, bulk of disease, and relative resistance to chemotherapy
Squamous carcinomas are generally sensitive to combinations that include a platinum agent with paclitaxel and/or gemcitabine[NCCN Bladder Cancer]
Adenocarcinomas tend to respond only transiently to regimens used for cancers of the gastrointestinal tract
Small-cell anaplastic cancer of the bladder is an aggressive malignancy compared with urothelial carcinoma of the bladder[Moretto 2013]
Most useful regimens involve combinations that include a platinum complex plus etoposide (with or without a taxane); doxorubicin, cyclophosphamide, and vincristine; or the addition of gemcitabine or an oxazophorine