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Neoadjuvant chemotherapy

Half of patients having radical cystectomy alone will develop metastatic disease – hence rationale for neoadjuvant chemotherapy.

Arguments for: Arguments against:
·       Improves overall survival by 5 %

·       Chemo better tolerated pre-cystectomy

·       Treats micrometastatic disease early

·       May downstage bulky tumours and improve resectability

·       Excellent outcomes for ypT0 patients

 

 ·       Delay to definitive surgery, particular for non responders

·       Some patients frailer and more debilitated after chemo

·       1 % mortality rate from chemotherapy

·       Unclear efficacy in variant histology

 

 

 

Must be cisplatin based. No benefit for carboplatin found in data.

  • Small evidence available suggests no survival benefit for carboplatin. If ineligible for cisplatin, should be proceed straight to surgery.

 

There are no validated predictive factors or clinical characteristics currently available to determine a better or worse response to platinum based chemo.

 

Efficacy:

  • Meta-analyses confirm overall survival at 5 years improved by 5 – 8 %
  • About 30 % may have a complete pathological response (these patients have significantly improved survival; cf. 10 -15 % pT0 with resection only)

 

Retrospective data suggests no difference between gem-cis and MVAC.

 

MVAC

Methotrexate

  • Inhibits dihydrofolate reductase -> reducing purine formation inhibiting DNA synthesis
  • Myelosuppression, pulmonary fibrosis, hepatotoxicity, nephrotoxicity, mucositis

Vinblastine

  • Vinka alkaloid which is a microtubule inhibitor
  • Neurotoxicity, ileus, bronchospasm, uric acid nephropathy

Doxorubicin (Adriamycin)

  • Anthracycline which is a topoisomerase inhibitor
  • Cardiac toxicity, myelosuppression

Cisplatin

  • Platinum based agent causing DNA cross-linking
  • Nephrotoxicity, peripheral neuropathy, ototoxicity/tinnitus, myelosuppression, heart failure

 

Dose dense (ddMVAC) has been adapted from metastatic treatment and used in the neoadjuvant setting.

  • Better tolerated
  • Cycled every 2 weeks (cf. 4 week cycles standard MVAC), quicker cystectomy
  • Potentially better efficacy

 

Gem-cis

Gemcitabine

  • Incorporated into DNA and directly inhibits DNA synthesis
  • Associated with myelosuppression

 

Gem-cis is less toxic than traditional MVAC. 4 x 3 week cycles.

 

VESPER trial 2022 (ddMVAC 6 cycles vs gem-cis 4 cycles, 88 % neoadjuvant)

  • Similar ypT0 rates (36 and 42 %)
  • Progression free survival better for ddMAVC at 3 years (only in neoadj subgroup) cf. gem-cis
  • More side effects for ddMVAC (asthenia, GIT)
  • Less patients completed planned ddMVAC (60 %) cf. gem-cis (84 %)

 

Key ineligibilities for cisplatin:

  • Performance status
  • Nephrotoxicity (traditionally eGFR > 60 required, may be able to split dose)
  • Heart failure (need significant fluid loads during treatment)
  • Neurotoxicity / hearing loss / tinnitus
  • Peripheral neuropathy

 

When to restage?

Prior to cystectomy – generally repeat CT after chemo and before cystectomy to ensure no progression.