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)

Germline testing is recommended at the time of initial diagnosis and during recurrence in bladder cancer patients. Information about family and personal history of cancer, as well as any known germline variants, should be collected at the time of diagnosis.  

Somatic tumor testing, which includes FGF3 alterations at the time of initial diagnosis and during recurrence, microsatellite instability-high (MSI-H), mismatch repair (MMR) status, and immunohistochemistry (IHC) for HER2 are tests recommended for all patients with locally advanced unresectable or metastatic bladder cancer. Regarding somatic tumor testing, it has been found to have predictive response to therapy with Erdafitinib, which is an FGFR inhibitor.

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
• CIS – “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:
  • Certain histopathologic subtypes, 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. Gemcitabine intravesical system may be a treatment option for patients with BCG-unresponsive, high-risk non-muscle invasive bladder cancer with CIS (with or without papillary) tumors. 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 or Nogapendekin alfa inbakicept-pmln plus BCG may be given as treatment. Nadofaragene firadenovec-vncg is a non-replicating adenoviral vector-based gene therapy. Nogapendekin alfa inbakicept-pmln is an immune cell-activating interleukin-15 superagonist which is used in combination with BCG. Pembrolizumab is a programmed cell death protein 1 (PD-1) inhibitor. 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. Perioperative chemotherapy is not recommended in patients who are not candidates for Cisplatin. Neoadjuvant chemotherapy is preferred over adjuvant-based chemotherapy.  For patients with muscle invasive bladder cancer, neoadjuvant or adjuvant regimens include the preferred regimen DDMVAC (dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin) with growth factor support for 3-6 cycles. Useful neoadjuvant therapies in certain circumstances include Gemcitabine and Cisplatin for 4 cycles. Other recommended regimen for adjuvant therapy in patients who have not previously received platinum-based neoadjuvant therapy. Other recommended adjuvant therapies in patients with or without previous treatment with platinum-based neoadjuvant therapy include Nivolumab and Pembrolizumab. The preferred regimen for perioperative or sandwich therapy is Gemcitabine plus Cisplatin plus Durvalumab before cystectomy followed by Durvalumab after cystectomy. 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.  

Recommended First-line Therapy for Patients with Locally Advanced or Metastatic Bladder Cancer  

The preferred regimens are Enfortumab vedotin-ejfv and Pembrolizumab. Other recommended regimens include: 

• Gemcitabine and Cisplatin followed by Avelumab maintenance therapy or
• Gemcitabine, Cisplatin, and Nivolumab followed by Nivolumab maintenance therapy or
• DDMVAC with growth factor support by Avelumab maintenance therapy

Useful regimens for Cisplatin-ineligible patients include:

• Gemcitabine and Carboplatin followed by Avelumab maintenance therapy or
• Pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma and are not eligible for any platinum-based chemotherapy or
• Atezolizumab for patients with programmed cell death-ligand (PD-L1)-expressing tumor or those not eligible for any platinum-based chemotherapy regardless of PD-L1 expression

Recommended Second-line Therapy for Patients with Locally Advanced or Metastatic Bladder Cancer  

Preferred regimens in patients with previous immunotherapy and Enfortumab vedotin-ejfv therapy without previous chemotherapy include:

• DDMVAC with growth factor support
• Gemcitabine and Cisplatin
• Gemcitabine and Carboplatin
• Biomarker-directed therapy:
  • Erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations
  • Fam-trastuzumab deruxtecan-nxki for patients with HER2-positive, IHC 3+ tumors

Other recommended regimens in patients with previous immunotherapy for Enfortumab vedotin-ejfv therapy without previous chemotherapy include Paclitaxel or Docetaxel and Gemcitabine. While regimens which may be useful in certain circumstances in patients with previous immunotherapy and Enfortumab vedotin-ejfv therapy without previous chemotherapy include Gemcitabine, Cisplatin, Nivolumab.  

Preferred regimens in patients with previous chemotherapy and without previous immunotherapy or Enfortumab vedotin-ejfv include:

• Pembrolizumab
• Enforumab vedotin-ejfv and Pembrolizumab
• Enforumab vedotin-ejfv
• Nivolumab
• Avelumab
• Biomarker-directed therapy:
  • Erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations
  • Fam-trastuzumab deruxtecan-nxki for patients with HER2-positive, IHC 3+ tumors

Other recommended regimens in patients with previous immunotherapy or Enfortumab vedotin-ejfv therapy include Paclitaxel or Docetaxel and Gemcitabine.  

Regimens which are useful in certain circumstances in patients with previous chemotherapy and without previous immunotherapy or Enfortumab vedotin-ejfv therapy include:

• DDMVAC with growth factor support
• Ifosfamide, Doxorubicin and Gemcitabine
• Gemcitabine and Paclitaxel
• Gemcitabine and Cisplatin

Re-treatment with platinum (eg Cisplatin, Carboplatin) may be considered in patients with previous chemotherapy and without previous immunotherapy or Enfortumab vedotin-ejfv therapy if the patient is still platinum eligible with progression-free survival >12 months after platinum therapy.  

Preferred regimens in patients with previous immunotherapy and without previous chemotherapy or Enfortumab vedotin-ejfv therapy include:

• Enfortumab vedotin-ejfv
• Enfortumab vedotin-ejfv and Pembrolizumab
• Gemcitabine and Carboplatin
• Gemcitabine and Cisplatin
• DDMVAC with growth factor support
• Biomarker-directed therapy:
  • Erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations
  • Fam-trastuzumab deruxtecan-nxki for patients with HER2-positive, IHC 3+ tumors

Other recommended regimens in patients with previous immunotherapy and without previous chemotherapy or Enfortumab vedotin-ejfv therapy include Paclitaxel or Docetaxel and Gemcitabine.  

Regimens which are useful in certain circumstances in patients with previous immunotherapy and without previous chemotherapy or Enfortumab vedotin-ejfv therapy include:

• Gemcitabine, Cisplatin and Nivolumab
• Ifosfamide, Doxorubicin and Gemcitabine
• Gemcitabine and Paclitaxel

Preferred regimens in patients with previous chemotherapy and immunotherapy and without previous Enfortumab vedotin-ejfv therapy include:

• Enfortumab vedotin-ejfv
• Biomarker-directed therapy:
  • Erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations
  • Fam-trastuzumab deruxtecan-nxki for patients with HER2-positive, IHC 3+ tumors

Other recommended regimens in patients with previous chemotherapy and immunotherapy and without previous Enfortumab vedotin-ejfv therapy include:

• Enfortumab vedotin-ejfv and Pembrolizumab
• Paclitaxel or Docetaxel
• Gemcitabine
• Gemcitabine and Cisplatin
• DDMVAC with growth factor support
• Ifosfamide, Doxorubicin and Gemcitabine
• Gemcitabine and Paclitaxel

Regimen which may be useful in certain circumstances in patients with previous chemotherapy and immunotherapy and without previous Enfortumab vedotin-ejfv therapy include Sacituzumab govitecan-hzly. Regimens for patients with previous chemotherapy and immunotherapy and without previous Enfortumab vedotin-ejfv therapy are indicated for patients who have already received platinum-based chemotherapy and a checkpoint inhibitor, if eligible and are suitable for patients who have received a first-line platinum chemotherapy followed by a checkpoint inhibitor maintenance therapy or first-line therapy containing both platinum chemotherapy and an immune checkpoint inhibitor. 

Recommended Subsequent-line Systemic Therapy for Locally Advanced or Metastatic Bladder Cancer After Chemotherapy, Immunotherapy, and Enfortumab vedotin-ejfv Therapy  

Recommended subsequent-line systemic therapy is indicated in patients who have already received platinum-based chemotherapy and a checkpoint-inhibitor, if eligible and are suitable for patients who have received a first-line platinum chemotherapy followed by a checkpoint inhibitor maintenance therapy, or first-line therapy containing both platinum chemotherapy and an immune checkpoint inhibitor. Preferred regimens are biomarker-directed therapy such as Erdafitinib, which may only be used for patients with susceptible FGFR3 or FGFR2 genetic alterations, and Fam-trastuzumab deruxtecan-nxki for patients with HER2-positive, IHC 3+ tumors.  

Other recommended regimens include Gemcitabine, Paclitaxel or Docetaxel, Ifosfamide, Doxorubicin and Gemcitabine, and Gemcitabine with Paclitaxel. A regimen which may be useful in certain circumstances is Sacituzumab govitecan-hzly. 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

Chemoradiotherapy is a bladder-preserving approach which is an alternative to immediate cystectomy in patients with muscle invasive bladder cancer. For muscle invasive bladder cancer, radical radiotherapy is given using a radiosensitizer. Preferred radiosensitizing chemotherapy regimens include Cisplatin monotherapy, low-dose Gemcitabine, and 5-Fluorouracil (5-FU) and Mitomycin. Other recommended radiosensitizing chemotherapy include Cisplatin and 5-FU and Cisplatin and Paclitaxel. Radiosensitizing chemotherapy regimens which may be useful in certain circumstances but not used for curative-intent chemoradiotherapy for organ preservation include Docetaxel or Palitaxel, 5-FU, and Capecitabine.  

Conventional fractional radiation therapy with a radiosensitizer may be used as palliative therapy in patients with advanced or metastatic disease. The recommended regimens include Cisplatin (preferred), taxanes (Docetaxel, Paclitaxel), Fluorouracil monotherapy, Fluorouracil plus Mitomycin, low-dose Gemcitabine, or Capecitabine monotherapy.  

Concurrent chemoradiotherapy is an alternative option to radical cystectomy in patients with recurrent Ta–T1 disease (without extensive CIS) who have a history of BCG therapy and are ineligible for cystectomy. It is also recommended for patients in need of added tumor cytotoxicity. This is also the most appropriate for patients with solitary tumors, negative nodes, without extensive or multifocal CIS, without moderate or severe tumor-related hydronephrosis and with good pre-treatment bladder function. Concurrent chemoradiotherapy should be considered as potentially curative therapy for patients who are medically inoperable or for local palliation in patients with metastatic disease. 

Surgery

Transurethral Resection of Bladder Tumor (TURBT)  

TURBT is the standard treatment for non-muscle invasive bladder tumors (Ta, T1, CIS) 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 CIS 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 low-grade/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. Palliative RT dose is 30 Gy in 10 fractions or 21 Gy in 3 fractions. 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.