Bladder%20cancer Treatment

• Non-muscle invasive tumors management is directed at reducing recurrences and preventing progression to a more advanced stage
• Goals of therapy for muscle invasive lesions are to determine if the bladder should be removed or preserved without compromising survival, and 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

Intravesical Therapy

Intravesical Chemotherapy

• In low-risk patients, and those presumed to be at intermediate risk with previous low recurrence rate, a single, immediate, post-operative intravesical instillation of chemotherapy has been considered to be the standard and sufficient treatment
  
  • Shown to act by the destruction of circulating tumor cells resulting from TURB 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
  • 2 consecutive cycle inductions is 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 lymph-node-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-Guérin (BCG) Immunotherapy 

• Treatment option for patients with non-muscle invasive disease
  • Studies showed BCG after TURBT is superior to TURBT alone or TURBT with chemotherapy in preventing recurrence in non-muscle invasive bladder cancer
• May be considered in patients with stage IIIB muscle invasive bladder cancer with partial response after concurrent chemoradiotherapy

• Intravesical BCG regimen consists of 6-week induction course, followed by 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 is substantial local symptoms experienced during the maintenance therapy, dose reduction is encouraged
  • It has been shown in recent data that maintenance BCG therapy results in decreased rate of recurrence of non-muscle invasive disease
    • May also decrease 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 with diagnosed T2-T4a, cN0M0 muscle invasive bladder cancer
• For patients with muscle invasive bladder cancer, neoadjuvant or adjuvant regimens include:
  
  • Preferred regimens:
    • Gemcitabine and Cisplatin for 4 cycles or
    • DDMVAC (dose-dense Methotrexate, Vinblastine, Doxorubicin and Cisplatin) with growth factor support for 3 or 4 cycles
  • 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, 1st-line systemic therapy regimens include:
  • Preferred regimens for Cisplatin-eligible patients:
    • 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
  • 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 patients who are ineligible for Cisplatin-based systemic therapy include Ifosfamide, Doxorubucin, and Gemcitabine
• Checkpoint inhibitors such as Pembrolizumab (preferred), Nivolumab, Avelumab, Erdafitinib and Enfortumab vedotin are recommended as 2nd-line systemic therapy of locally advanced or metastatic bladder cancer after platinum-based therapy
  • Other recommended regimens include Paclitaxel or Docetaxel and Gemcitabine and Pembrolizumab and Enfortumab vedotin-ejfv
  • Conditional regimens that may be considered based on patient’s medical history include Ifosfamide + Doxorubicin + Gemcitabine, Gemcitabine + 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 2nd-line systemic therapy for locally advanced or metastatic bladder cancer after checkpoint inhibitor-based therapy include:
  • Preferred regimens for Cisplatin-eligible patients and without prior chemotherapy: Gemcitabine with Cisplatin or DDMVAC with growth factor support
  • Gemcitabine + 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 include:
  • Preferred regimens: Enfortumab vedotin or Erdafitinib
    • Erdafitinib 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