Bladder Cancer Guidelines

Bladder Cancer Fast Facts

• Begins in the urothelial cells lining the inside of the bladder
• Urothelial bladder carcinoma type (UBC) accounts for the majority of bladder cancer (~90%)¹
• It is the 6^th most common cancer in the U.S.; approximately 2.3% of men and women will be diagnosed in their lifetime²
• There is a strong male predominance, with male to female ratio of 4:1
• Cigarette smoking and environmental exposure account for >50% of cases³
• There is no standard or routine screening tests for UBC in asymptomatic individuals
• Work up for UBC is initiated with evidence of microscopic hematuria (≥ 3 RBC/HPF*)⁴ or gross hematuria
• Most common presenting symptoms include: painless hematuria (80% of patients), irritative symptoms and flank pain⁵

Bladder Cancer Risk Factors

• Smoking (> 50% attributed to exposure)
• Age (90% of diagnosis older 55yo)
• Sex (4:1 male to female ratio)
• Chronic infections and irritation
• Family history (two-fold increase)⁶
• Environmental exposure to arsenic, hair dye and industrial chemicals (account for 6.5% UBC diagnosis) ⁷

Bladder Cancer Testing

• Urinalysis (looks for blood in the urine)
• CT or MR Urogram
  • Evaluates upper urinary tract for lesions (kidneys and ureters)
  • Use of iodinated contrast acceptable with GFR*≥ 45⁸
• Cystoscopy
  • In-office evaluation to look for bladder abnormalities
• Urine Cytology
  • Looks for abnormal or cancer appearing cells
  • Not used as a primary method for diagnosis; limited sensitivity
• Routine blood work: Complete Blood Count, and Metabolic Profile
  • Obtain prior to imaging with iodinated contrast
• Transurethral resection or biopsy of suspicious lesion
  • If tumor is suspected on imaging or seen on cystoscopy, additional biopsy in the operating room is necessary

Bladder Cancer Prognosis

While the overall 5-year survival among all bladder cancer patients is around 76%, this number varies however, based on tumor stage, histopathology, grade and response to treatment.⁹

Bladder Cancer Tumor Histology

Bladder cancer histology can be classified as urothelial or non-urothelial. While majority of bladder cancer is considered urothelial (~90%),  non urothelial variants do exist including:

• Squamous Cell Carcinoma (2.7%)¹⁰
  • Adenocarcinoma (1.4%)¹⁰
  • Neuroendocrine differentiation (i.e. Small Cell Carcinoma; 1%)¹⁰

Staging

Bladder cancer staging is based depth of invasion, starting with superficial inner lining, and progressing through lamina propria(T1) and muscle layers of the bladder (T2). Increasing involvement of the fat surrounding the bladder (T3) and nearby structures (T4), or lymph nodes (N+) designates advanced bladder cancer.

Grade

Grade is a categorization of a continuously increasing nuclear atypia, mitotic activity, and pattern of urothelial cancer cells.¹¹ Tumor grade is an essential risk factor for progression and disease management in non-muscle invasive bladder cancer (NMIBC).

• Cells considered low grade show minimal deviation from the morphology of the normal urothelium
• Cells considered high grade display high nuclear atypia, lack of cohesion, and cell disorder

Bladder Cancer Survival Rates

Survival is based on grade, stage of disease, and tumor histology. The reported 5-year OS* in patients diagnosed with bladder cancer¹²:

Available Predictive Tools

• EORTC model (European Organization for Research and Treatment of Cancer) allows providers to calculate the probability of recurrence and progression over 1-5 years based on patient’s clinical and tumor characteristics. This predictive model can only be utilized for Stage 0/I disease (NMIBC)¹³.
• IBCNC model (International Bladder Cancer Nomogram Consortium) predicts the risk of recurrence at 5 year following radical cystectomy and pelvic lymph node dissection. Nomogram accuracy (75%) exceeds AJCC TNM staging alone (68%)¹⁴.
• MSKCC model (Memorial Sloan-Kettering Cancer Center) postoperative nomogram predicting risk of recurrence after radical cystectomy. Similar to IBCNC model, it outperforms AJCC TNM staging in accuracy¹⁵.  Both IBCNC and MSKCC models are used in muscle invasive bladder cancer (pT2 and higher).

Bladder Cancer Management

Management of UBC is dependent on stage of disease at presentation, as well as consideration of patient goals and side effects of treatment. Many times, the best option may include more than one type of treatment or combination of different treatments (chemotherapy, radiation, and surgery).

Treatment of Non-Muscle Invasive Bladder Cancer

• Bladder preservation is key
  • Optimal removal of all visible lesions with transurethral resection followed by installation of intravesical chemotherapy or immunotherapy BCG (Bacillus Calmette-Guerin)
  • Treatment duration and frequency vary based risk stratification¹⁶

Treatment of Muscle Invasive Bladder Cancer

• Upfront neoadjuvant chemotherapy followed by radical cystectomy remains the gold standard care for locally invasive Stage II-IV non metastatic UBC
  • Receipt of neoadjuvant chemotherapy (NAC) prior to surgery improves 5-year OS and disease free survival by 5-10%¹⁷
  • Bladder preservation therapy is a reasonable option for patients medically unfit for surgery or seeking an alternative. It is comprised of: Aggressive resection of all visible tumorChemotherapyRadiation

Treatment of Metastatic Bladder Cancer

• Cisplatin containing combination chemotherapy is standard in advanced or metastatic UBC
  • Patients not eligible for cisplatin-based chemotherapy, are eligible for immunotherapy such as Atezolizumab¹⁸ or Pembrolizumab¹⁹

Considerations of Specific Treatment Modalities

• Surgery
  • Radical cystectomy (RC)with bilateral pelvic lymph node dissection (PLND) is the standard of care in MIBC. Surgery is also an option for patients with persistent high-grade cancer after several courses of intravesical therapy
  • Upon removal of the bladder, urinary continuity may be reconstructed as a continent diversion: neobladder vs catheterisable pouch (i.e., Indiana pouch), or incontinent diversion: ileal conduit
  • Continent urinary diversion such as neobladder and catheterisable pouch experience 32% and 38% higher risk of complications compared to ileal conduit, respectively
  • Patient selection is key to optimize right patient for the right surgery²⁰

• Radiation
  • There is no evidence demonstrating advantage of adjuvant radiation after RC/PLND
  • Bladder preservation therapy for MIBC via trimodal therapy (TMT) (transurethral resection, radiation, and chemotherapy) is reserved for patients who are:
    • Medically unfit for surgery
    • Seeking alternative to RC
  • To be considered eligible for TMT, patients must have tumor that can undergo visible resection, no evidence of hydronephrosis (blockage of urine from kidneys), no invasion into prostate or diffuse carcinoma in situ
  • 5-year OS with trimodal therapy range 36-72%²¹
  • 1:5 patients will require removal of bladder due to recurrence after TMT²²

• Systemic Therapies
  • Cisplatin-gemcitabine (GC) or accelerated methotrexate, vinblastine, adriamycin and cisplatin (ddMVAC) are most widely given NAC regimens
  • 3-year progression free survival was 65% in the ddMVAC group vs 56% in gemcitabine/cisplatin group. Despite improvement in PFS, there were more serious grade ≥ 3 complication in ddMVAC group²³
  • Patients who did not receive NAC prior to surgery may be eligible for adjuvant therapy with GC or ddMVAC. Patients who were eligible to receive adjuvant chemotherapy experience a 23% decreased risk of mortality at 5 years, and 36% decreased risk of recurrence²⁴. Again, selection is key, as not many patients after surgery can undergo adjuvant chemotherapy

Bladder Cancer Surveillance Following Therapy

Surveillance following treatment in bladder cancer is dependent on stage of disease and treatment modality:

• Surveillance NMIBC
  • Dependent on the risk stratification of recurrence and progression determined by pathology and work up, patients are monitored every 3 to 6 months for the first 2 years with longer follow up thereafter
  • Surveillance is performed via urine cytology, cystoscopy and imaging (CT or MR Urogram)

• Surveillance Following Surgery
  • No single follow-up plan is appropriate for all patients, the recommendations provided maybe modified based on individual patient, and reassessment of disease activity should be performed in patients with new or worsening symptoms
  • Patients with MIBC post-surgery require CTU or MRU with CT chest every 3-6 months first 2 years, with CBC, CMP, and LFT²⁵

• Surveillance During Chemo/Immunotherapy
  • CTU or MRU imaging every 3-6 months or any clinical change or symptoms
  • CT chest every 3-6 months
  • Blood work including CBC, CMP and LFT every 1-3 months with additional bloodwork per therapy and side-effect profile²⁵

*RBC/HPF; Red Blood Cells per High Power Field
GFR: Glomerular Filtration Rate
OS: Overall Survival

References

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Author Bio

Dr. Laura Bukavina is a urologic oncology fellow at Fox Chase Cancer Center, with focus in bladder and kidney cancer. She is an incoming urologic oncology faculty at University Hospitals Cleveland Medical Center/Case Western Reserve University. Dr. Bukavina’s career commitment is to advance the understanding and treatment of bladder cancer through integration of science and surgery. She continues her work with support from American Urologic Association and Bladder Cancer Advocacy Network grants focusing on microbiome modulation, tumor microenvironment and treatment response. The goal of her research is to understand responses to therapy based on unique patient immune environment and interaction with host bacteria. More information about her research can be seen here: https://www.urotoday.com/video-lectures/bladder-cancer/video/2629-microbiome-research-in-bladder-cancer-laura-bukavina.html

Twitter: @LauraBukavinaMD