Bladder Cancer: Drug Therapy

Therapy recommendations

  • Depending on prognostic criteria, adjuvant therapy for superficial (superficial) bladder carcinomas is indicated after transurethral resection (TUR); it is dispensable for well-differentiated noninvasive primary tumors. Cytostatic agents (cisplatin, doxorubicin, mitomycin C, epirubicin) and the immunomodulator BCG (Bacillus Calmette-Guérin) are available. While in patients at low risk of progression chemotherapy or immunotherapy is considered equivalent, in patients at high risk of progression (G 3 tumors, recurrent tumors) intravesical (“introduced into the urinary bladder“) treatment with BCG is preferred. A meta-analysis was able to show a reduction in the risk of recurrence by postinterventional early instillation 8d. h. in the first 24 hours after endourological tumor resection) of almost 40%.
  • Non-muscle invasive bladder cancer (NMIBC):
    • For urothelial carcinoma of the urinary bladder in the low-risk stage, no further adjuvant chemotherapy instillation should be performed after TUR and early instillation [S3 guideline].
    • In intermediate- or high-risk cases, instillation therapy with mitomycin C or BCG (see below) is reasonable following resection.
    • In case of recurrence after BCG therapy, cystectomy is required.
  • Muscle-invasive bladder carcinoma:
    • Standard surgery for curative therapy is radical cystectomy
    • Neoadjuvant chemotherapy (NACT; i.e., prior to surgical therapy; 3-4 cycles of cisplatin-containing combination chemotherapy): may improve survival of patients with muscle-invasive bladder cancer (≥ T2) after cystectomy.Neoadjuvant cisplatin-containing chemotherapy (use of cytostatic agents to reduce tumor mass prior to surgical intervention) is recommended by the European Association of Urology (EAU) for nonmetastatic bladder cancer. This approach sol provide a survival benefit of 6% to 8% over cystectomy alone.
  • If early cystectomy is not indicated in patients with high-risk urothelial carcinoma of the urinary bladder, BCG instillation therapy should be performed. In the case of complete remission after the induction phase, maintenance therapy should also be given for a period of at least 1 to a maximum of 3 years [S3 guideline].
  • In carcinoma-in-situ (Tis), intravesical therapy with BCG is indicated after TUR (BCG therapy according to the induction and maintenance regimen [S3 guideline])… Full remission over 5 years is achieved in about 70% of patients. If this therapy fails, radical cystectomy is indicated.
  • In non-muscle-invasive bladder cancer (NMIBC) with a low degree of differentiation (“high grade”), intravesical BCG therapy is the gold standard or pillar of bladder-preserving therapy. This should be given as maintenance therapy for at least one year.
    • In the presence of a high-risk constellation, cystectomy for high-grade bladder carcinoma-even without evidence of muscle invasion (ingrowth into the muscle)-is a proven and safe procedure.
    • Older patients with NMIBC appear to be at higher risk of recurrence and progression. Therefore, they should be treated and monitored as carefully as younger patients.
  • BCG therapy should be administered according to the following regimen [S3 guideline]:
    • Induction cycle with 6 BCG instillations at weekly intervals.
    • Maintenance therapy with 3 BCG instillations each at weekly intervals at 3, 6 and 12 months after the start of the induction cycle
    • In high-risk tumors, a further 3 BCG instillations at weekly intervals each 18, 24, 30 and 36 months after the start of the induction cycle after weighing the benefits and risks or side effects.
  • Patients with pT1 G 3 tumors are a special risk group, because the tumor often becomes progressive (progressive). Here, after complete TUR, an attempt at organ-preserving therapy using intravesical BCG instillation prophylaxis is warranted; in the event of recurrence (recurrence of disease) of pT1G3 within 3-6 months, radical cystectomy is indicated.
  • Metastatic carcinoma of the urinary bladder:
    • Chemotherapy alone (containing cisplatin) is indicated only in the presence of distant metastases.
      • “For first-line chemotherapy, restaging should be performed every 2-3 cycles (cycles of 3-4 weeks)” [S3 guideline].
      • First-line therapy: cisplatin-containing combination chemotherapy consisting of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) or gemcitabine and cisplatin (GC).
        • “Cisplatin-fit patients”: combination treatment of gemcitabine plus cisplatin (GC).
        • “Cisplatin-unfitting patients” (WHO or ECOG performance status (ECOG-PS) at 2 or above or. the Karnofsky PS at 70% or below; reduced general health; impaired renal function (glomerular filtration rate ≤ 60 ml/min); audiometric hearing loss grade ≥ 2 CTCAE (“Common Terminology Criteria for Adverse Events”); peripheral neuropathies grade ≥ 2 CTCAE; and heart failure NYHA(“New York Heart Association”) class > 3): each parameter mentioned is considered an exclusion criterion.
          • Glomerular filtration rate in the range of 40-60 ml/min – the recommendation – can be treated with “cisplatin in divided doses.

          In “cisplatin-naïve patients” with metastatic urothelial carcinoma is not yet defined in the current guideline version 2.0: For therapy, the checkpoint inhibitors atezolizumab or pembrolizumab are recommended in the presence of proven high PD-L1(“programmed cell death-ligand 1”) expression (see below PD-1 immune checkpoint inhibitors).

          • Other prerequisites for their therapy are required:
      • Second-line therapy
        • After prior platinum-containing therapy, an immune checkpoint inhibitor may be used, with a higher level of recommendation for pembrolizumab than for atezolizumab or nivolumab.
        • If immune checkpoint inhibitors are contraindicated, vinflunine should be used.
    • PD-1 immune checkpoint inhibitors:
      • Pembrolizumab (PD-1 (programmed cell death 1 protein) inhibitor) for monotherapy in adults with locally advanced or metastatic urothelial Ca after prior platinum-based therapy and in adults ineligible for cisplatin-based therapy.In the second-line setting, there is evidence of substantial added benefit for pembrolizumab (IQWiG, 2017).
      • Atezolizumab (PD-1 (programmed cell death 1 protein) inhibitor) as monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma Note: Preliminary data from an ongoing first-line clinical trial of locally advanced or metastatic urothelial carcinoma show decreased survival with atezolizumab monotherapy compared with platinum-based chemotherapy in patients whose tumors show low PD-L1(programmed death ligand 1) expression (<5% of immune cells staining positive for PD-L1):
        • The indication of atezolizumab for first-line treatment of urothelial carcinoma in patients unsuitable for treatment with cisplatin is therefore restricted: it may now only be used for first-line treatment if the patient has high PD-L1 expression (≥ 5%).
        • The use of atezolizumab after prior chemotherapy remains unchanged.
      • Nivolumab – approved in Germany as two-line therapy after platinum-containing pretreatment without consideration of a biomarker.
  • See also under “Further therapy”.

Further notes

  • BCG therapy: “As a side effect (frequency up to 1%), disseminated BCG infection (dissemination; lat. disseminare “to sow”) may occur, which can be latent and flare up again after years. When flare-ups occur in particular granulomatous pneumonitis (collective term for any form of pneumonia (pneumonia), which does not affect the alveoli (alveoli), but the interstitium or intercellular space), abscess (encapsulated collection of pus), infected aneurysm (pathological (pathological) bulges of vessel walls), infected implants or grafts, and infection of the surrounding tissue.”
  • Low-grade urothelial carcinoma (maximum diameter 5-15 mm) of the upper urinary tract: UGN-101 consisting of mitomycin and a sterile hydrogel and installed in renal pelvis and calices, 59% of cases showed a complete response 3 months after initiation of therapy.Common adverse events were: Ureteral stenosis (ureteral obstruction; 44%), urinary tract infections (32%), hematuria (blood in the urine; 31%), flank pain (30%), and nausea (24%); there were no deaths. Limitation: no control group!
  • For prevention of osteonecrosis of the jaw, before administration of bisphosphonates or denosumab [S3 guideline]
    • A dental examination and, if necessary, dental rehabilitation as well as
    • An instruction and motivation of the patient to particularly careful oral hygiene take place.
  • In non-muscle invasive bladder carcinoma (NMIBC) with a low degree of differentiation (“high grade”), recurrence is expected in approximately 50% of cases after intravesical BCG therapy. In such cases, radical cystectomy (RC) is currently indicated. In one study, a further conservative therapy attempt in the form of intravesical salvage therapy (IVT/”salvage therapy”) was made in such cases. This procedure did not negatively affect the histopathological outcome or the 5-year survival rate. Compared with the RC group, the IVT patients were able to preserve the urinary bladder 1.7 years longer. Patients whose tumor had progressed to stage cT1 or who had lymphatic involvement should be excluded from these procedures – these patients should undergo radical cystectomy immediately.The study must be interpreted with caution because it is a retrospective study.
  • Adjuvant chemotherapy after cystectomy:In one study, overall survival (OS) was assessed using propensity score analyses, i.e., patient groups were matched on all parameters. This showed that the rate for 5-year OS was 37.0 versus 29.1% (hazard ratio 0.70; p < 0.001; this association was consistent in all subgroups between adjuvant chemotherapy and better survival.
  • Advanced urothelial carcinoma: First-line adjuvant therapy with a PD-L1 inhibitor, when combined with standard chemotherapy, can prolong progression-free survival by approximately two months and overall survival (OS) by nearly two and a half months. Limitation: no conclusive results are yet available for overall survival.
  • Locally advanced or metastatic bladder cancer: maintenance therapy with avelumab after first-line chemotherapy if disease remains stable for at least four weeks after discontinuation of cytostatic agents: Follow-up was a median of 19.6 with avelumab + BSC and 19.2 months with BSC alone. Participants survived a median of 21.4 months with avelumab treatment and a median of 14.3 months in the comparator arm, a difference of 7.1 months in overall survival.
    • Maintenance therapy with avemulab prolonged survival in a phase III study of patients with locally advanced or metastatic urothelial carcinoma, with 1-year survival increasing from 58.4% to 71.3%.