Bladder Cancer Management

Evaluation

Tumor specimen should be evaluated as follows:

• Depth of invasion (categories pT2 vs pT3a, pT3b, or pT4)
• Margins with special attention pain to the radial margin, prostate, ureter, urethra and peritoneal fat, and uterus and vaginal top
• Histological subtype, if it has clinical implications
• Extensive lymph node representation (>9)
• Bladder wall blood vessel invasion (optional evaluation)
• Pattern of muscle invasion (optional evaluation)

Transurethral Resection of Bladder Tumor (TURBT)  

TURBT with a bimanual examination under anesthesia is performed to resect visible tumor, to sample muscle within the area of the tumor, and to assess whether muscle invasion has occurred, although specimen collection may be omitted in patients with documented low-grade Ta disease. The main goal is to make the right histopathological diagnosis and staging, as it is essential in the diagnosis and management decision-making process. Specimen collection adjacent to a papillary tumor or prostate urethral biopsy may be considered for suspected or known CIS. Repeat TURBT within 6 weeks may be done in patients with suspected papillary lesions if there is incomplete initial resection, absence of muscle in the collected specimen (for high-grade disease), presence of large (≥3 cm) or multifocal lesions, or any T1 lesions. Repeat TURBT may also be done in patients with suspected sessile or muscle invasive tumor if there is absence of muscle in the collected specimen (for high-grade disease), any T1 lesions, resection done restricted further evaluation for staging, incomplete resection, and if trimodality bladder preservation therapy (combination of TURBT, chemotherapy, and radiotherapy) is being considered.  

Pathologic Staging  

The 8th edition Tumor, Node, Metastasis (TNM) staging system by the American Joint Committee on Cancer (AJCC) is the most commonly used staging system. Grading the tumor is an important prognostic indicator with regard to the potential for disease recurrence and progression. After stage and grade have been identified, treatment decisions are based on the depth of invasion and extent of disease.

Primary Tumor  

• Tx – Tumor size cannot be assessed
• T0 – No primary tumor present
• Ta – Non-invasive papillary carcinoma
• Tis – “Flat tumor” or urothelial CIS
• T1 – Papillary tumor invading the lamina propria or subepithelial connective tissue
• T2 – Tumor is in the muscularis propria or muscles
  • pT2a – Tumor is in the inner half or superficial muscularis propria
  • pT2b – Tumor is in the outer half or deep muscularis propria
• T3 – Tumor is in the perivesical tissue
  • pT3a – Microscopically
  • pT3b – Macroscopically (extravesical mass)
• T4 – Extravesical tumor is in any of the following: Prostatic stroma, seminal vesicles, uterus, vagina,          pelvic wall, abdominal wall
  • T4a – Extravesical tumor is in the prostatic stroma, seminal vesicles, uterus, vagina
  • T4b – Extravesical tumor is in the pelvic wall, abdominal wall

Regional Lymph Node (LN) Evaluation (N)  

Regional lymph node evaluation consists of assessment of both primary and secondary drainage regions. Distant lymph nodes are all other nodes that are above the bifurcation. More than 9 lymph nodes should be investigated to reflect N0 appropriately.

• Nx – Regional lymph nodes cannot be assessed
• N0 – Absence of regional lymph nodes
• N1 – Presence of a single regional LN metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral LN)
• N2 – Several regional LN metastases in the true pelvis (perivesical, obturator, internal and external iliac, or sacral LN)
• N3 – LN metastasis to the common iliac LN

Metastatic Disease (M)

• M0 – Distant metastasis is not present
• M1 – Presence of distant metastasis
  • M1a – Distant metastasis is limited to lymph nodes beyond the common iliacs
  • M1b – Non-LN distant metastasis

AJCC Pathologic Staging or Groups

American Urological Association (AUA) Risk Stratification for Non-Muscle Invasive Bladder Cancer  

The AUA risk stratification for non-muscle invasive bladder cancer is essential in facilitating treatment recommendations. Patients may have concerning features which can affect the management.  

Low-risk tumors are characterized by any of the following:

• Papillary urothelial neoplasm of low malignant potential (PUNLMP)
• Primary, solitary, low-grade Ta tumor ≤3cm

Features of intermediate-risk tumors include:

• Recurrence of low-grade Ta tumor within 1 year
• Low-grade T1 tumor
• Solitary low-grade Ta tumor >3 cm
• Low-grade multifocal Ta tumor
• Solitary, high-grade Ta tumor ≤3 cm

High-risk tumors can be any of the following:

• CIS
• High-grade T1 tumor
• High-grade Ta >3 cm or multifocal tumor
• Very high-risk features include:
  • Any variant histology, lymphovascular invasion, or high-grade prostatic urethral involvement
  • G3 or high-grade tumor
  • Recurrent high-grade Ta tumor
  • Multiple, recurrent and large (>3 cm) Ta G1G2 tumors
  • High-grade tumor with Bacillus Calmette-Guerin (BCG) treatment failure

World Health Organization (WHO) Grading  

The 1973 WHO classification is the widely used classification for grading of non-muscle invasive urothelial neoplasms. In 2004, members of WHO and the International Society of Urological Pathology (ISUP) published and recommended a revised consensus classification for papillary neoplasms. The 2004 WHO classification is yet to be validated by clinical trials; therefore, tumors are graded using both the 1973 and 2004 WHO classifications, though the majority of clinicians use the 2004 classification.  

1973 WHO Classification:

• Grade 1 (G1): Well-differentiated urothelial papilloma
• Grade 2 (G2): Moderately-differentiated urothelial papilloma
• Grade 3 (G3): Poorly-differentiated urothelial papilloma

2014/2016 WHO Classification (papillary lesion)

• Urothelial papilloma (completely benign lesion)
• PUNLMP
• Low-grade papillary urothelial carcinoma
• High-grade papillary urothelial carcinoma

Principles of Therapy

Non-muscle invasive tumors management is directed at reducing recurrences and preventing progression to a more advanced stage. The goals of therapy for muscle invasive lesions are to determine if the bladder should be removed or preserved without compromising survival, to determine if the primary lesion can be managed independently, or if patients are at high risk for distant spread requiring systemic approaches to improve the likelihood of cure. Therapy for patients with metastatic lesions should focus on prolongation and quality of life.  

Pharmacological therapy

Intravesical Therapy  

Intravesical Chemotherapy  

In low-risk patients and those presumed to be at intermediate risk with a previous low recurrence rate, a single, immediate, post-operative intravesical instillation of chemotherapy has been considered to be the standard and sufficient treatment. It has been shown to act by the destruction of circulating tumor cells resulting from TURBT and by an ablative effect (chemoresection) on residual tumor cells at the resection site and on small, overlooked tumors. Although for other patients, it remains an incomplete treatment because of the considerable likelihood of recurrence and/or progression.

Induction therapy should be administered within 24 hours after TURBT to prevent tumor cell implantation and early recurrence. During induction, weekly installations are given for approximately 6 weeks, with 2 consecutive cycle inductions being the maximum if without complete response.  

Gemcitabine and Mitomycin are the most widely used agents for intravesical chemotherapy. Gemcitabine is more preferred than Mitomycin based on toxicity profiles and cost. Alternative options to Gemcitabine and Mitomycin include Epirubicin, Valrubicin, Docetaxel, or sequential Gemcitabine/Docetaxel or Gemcitabine/Mitomycin. Adjuvant Cisplatin combination chemotherapy after radical cystectomy is considered for patients with a diagnosis of muscle invasive or LN-positive urothelial bladder cancer for whom neoadjuvant chemotherapy was not suitable. Adjuvant intravesical chemotherapy should be initiated 3–4 weeks after TURBT.

Intravesical Bacillus Calmette-Guerin (BCG) Immunotherapy  

Intravesical bacillus Calmette-Guérin (BCG) immunotherapy is a treatment option for patients with non-muscle invasive bladder cancer. Studies showed that BCG after TURBT is superior to TURBT alone or TURBT with chemotherapy in preventing recurrence in non-muscle invasive bladder cancer. It may also be considered in patients with stage IIIB muscle invasive bladder cancer with partial response after concurrent chemoradiotherapy. The intravesical BCG regimen consists of a 6-week induction course, followed by a maintenance dose with 3-weekly installations at 3, 6, 12, 18, 24, 30, and 36 months. For patients with intermediate-risk, maintenance is given ideally for 1 year, while for those with high-risk non-muscle invasive disease, it is given for 3 years. If there are substantial local symptoms experienced during maintenance therapy, dose reduction is encouraged. It has been shown in recent data that maintenance BCG therapy results in a decreased rate of recurrence of non-muscle invasive disease and may also decrease the risk for tumor progression in high- and intermediate-risk tumors. Absolute contraindications include patients with gross hematuria or symptomatic UTI, after traumatic catheterization, and 2 weeks after TURBT.

Systemic Therapy  

For patients with BCG-unresponsive non-muscle invasive bladder cancer with CIS, Pembrolizumab or Nadofaragene firadenovec-vncg may be given as treatment. Neoadjuvant chemotherapy using a Cisplatin combination regimen before radical or partial cystectomy or radiotherapy is recommended in patients diagnosed with T2–T4a, cN0M0 muscle invasive bladder cancer. For patients with muscle invasive bladder cancer, neoadjuvant or adjuvant regimens include preferred regimens such as Gemcitabine and Cisplatin for 4 cycles or DDMVAC (dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin) with growth factor support for 3 or 4 cycles, while an alternative regimen is CMV (Cisplatin, Methotrexate, and Vinblastine) for 3 cycles. For patients with locally advanced or metastatic urothelial bladder cancer who are otherwise physically fit and have adequate renal function, a Cisplatin-based chemotherapy regimen is suggested. For patients with locally advanced or metastatic bladder cancer, first-line systemic therapy regimens include preferred regimens for Cisplatin-eligible patients such as Gemcitabine with Cisplatin followed by Avelumab maintenance therapy or DDMVAC with growth factor support followed by Avelumab maintenance therapy.  

Preferred regimens in patients who are ineligible for systemic therapy with Cisplatin include Gemcitabine with Carboplatin followed by Avelumab maintenance therapy or Atezolizumab or Pembrolizumab may be considered in patients with programmed death-ligand 1 (PD-L1)-expressing tumor or those ineligible for any platinum-containing chemotherapy regardless if positive for PD-L1 expression. Another option is Pembrolizumab and Enfortumab vedotin-ejfv. Other recommended regimens for patients who are ineligible for Cisplatin-based systemic therapy include Gemcitabine monotherapy or Gemcitabine with Paclitaxel. Conditional regimens that may be considered in these patients include Ifosfamide, Doxorubicin, and Gemcitabine.  

Checkpoint inhibitors such as Pembrolizumab (preferred), Nivolumab, Avelumab, Erdafitinib, and Enfortumab vedotin are recommended as second-line systemic therapy for locally advanced or metastatic bladder cancer after platinum-based therapy. Other recommended regimens include Paclitaxel or Docetaxel, Gemcitabine and Pembrolizumab, and Enfortumab vedotin-ejfv. Conditional regimens that may be considered based on the patient’s medical history include Ifosfamide plus Doxorubicin plus Gemcitabine, Gemcitabine plus Paclitaxel or Cisplatin, and DDMVAC with growth factor support. Erdafitinib may only be considered for patients with susceptible FGFR3 or FGFR2 genetic alterations. Enfortumab vedotin is indicated for Cisplatin-ineligible patients who have received ≥1 prior lines of therapy.  

Recommended second-line systemic therapy for locally advanced or metastatic bladder cancer after checkpoint inhibitor-based therapy includes preferred regimens for Cisplatin-eligible patients without prior chemotherapy such as Gemcitabine with Cisplatin or DDMVAC with growth factor support. Gemcitabine plus Carboplatin combination regimen and Enfortumab vedotin monotherapy are recommended for patients who are Cisplatin-ineligible and chemotherapy-naive. Other recommended regimens include Erdafitinib, Paclitaxel or Docetaxel, and Gemcitabine. Conditional regimens that may be considered include Gemcitabine and Paclitaxel or Ifosfamide/Doxorubicin/Gemcitabine combination therapy.  

Recommended subsequent-line systemic therapy for locally advanced or metastatic bladder cancer after platinum and checkpoint inhibitor therapy includes preferred regimens such as Enfortumab vedotin or Erdafitinib, and Erdafitinib, which may only be used for patients with susceptible FGFR3 or FGFR2 genetic alterations. Other recommended regimens include Gemcitabine, Paclitaxel or Docetaxel, Ifosfamide/Doxorubicin/Gemcitabine, Gemcitabine with Paclitaxel or Cisplatin, DDMVAC with growth factor support, and Sacituzumab govitecan. Pembrolizumab may also be considered in patients with high-risk non-muscle invasive bladder cancer with CIS unresponsive to BCG treatment and ineligible for cystectomy.

Bladder Cancer_Management 1

Surgery

Transurethral Resection of Bladder Tumor (TURBT)  

TURBT is the standard treatment for non-muscle invasive bladder tumors (Ta, T1, Tis) and cTa low-grade tumors, with the goal of removing all visible lesions. It is also a therapeutic option in patients with muscle invasive bladder tumor if tumor growth is limited to the superficial muscle layer and if re-staging biopsies are negative for invasive tumor. The strategy of resection depends on the size of the lesion; in small tumors (<1 cm in diameter), en bloc resection can be done, where the specimen contains the complete tumor plus part of the underlying bladder wall including the muscle. While for large tumors and suspected muscle invasive bladder cancer, resection is done in parts, which include the exophytic part of the tumor, the underlying bladder wall with the detrusor muscle, and the edges of the resection area. Separate resection of larger tumors provides good information about the vertical and horizontal extent of the tumor and helps to improve resection completeness.

Complete and correct TURBT is essential to achieve a good prognosis. An absence of detrusor muscle in the specimen is associated with a significantly higher risk of residual disease, early recurrence, and tumor understaging. Selected mapping biopsies and transurethral biopsy of the prostate must be considered if a sessile lesion or Tis or high-grade disease is suspected. A second TURBT is performed after 2–3 weeks of incomplete initial TURBT, if there is no detrusor muscle in the specimen after initial resection, with the exception of TaG1, and when a high-grade, primary CIS, T1 tumor, and possibly a Ta has been detected at the initial TURBT. A second TURBT can increase recurrence-free survival, improve outcomes after BCG treatment, and provide prognostic information.

Bladder Cancer_Management 2

• No previous bladder cancer that was intermediate- or high-risk
• A disease-free survival of at least 6 months
• Solitary papillary recurrence
• A tumor diameter of ≤3 mm

In patients with a history of small, Ta LG/G1 tumors, fulguration of small papillary recurrences on an outpatient basis can reduce the therapeutic burden and can be a treatment option.

Radiation Therapy

Radiation therapy (RT) is an alternative treatment for patients unfit for or opposed to radical surgery or for local palliative treatment in patients with metastatic disease. Preoperative RT prior to cystectomy may be considered in patients with invasive tumors. Adjuvant pelvic irradiation may be considered for patients with pT3/pT4 pN0–2 disease who recently underwent radical cystectomy with ileal conduit. Intraoperative RT may be considered in highly selected T4b cases, as well as in patients with tumors extending to the abdominal and/or pelvic wall. Palliative RT combined with radiosensitizing chemotherapy is recommended, especially in patients with metastasis or disease recurrence. The recommended dose is 1.8–2.0 Gy daily fractionation. Conventional or accelerated hyperfractionation of 39.6–50.4 Gy may be applied to the whole bladder with or without pelvic nodal irradiation. Absence of hydronephrosis and extensive CIS is a factor for positive treatment response.