1. General principles: Neoadjuvant cisplatin based chemo followed by radical cystectomy plus pelvic LN dissection is the standard of care for cisplatin eligible patients with muscle invasive bladder cancer. In patients with residual disease after surgery, who have a PDL1 of 1% or more, should be treated with nivolumab q 2w for 1 yr.
2. Prognosis: Median OS in NAC+ cystectomy--> 102 months versus 82 months if no NAC
5 yr OS 60% versus 50%( for cystectomy alone), 14% improvement in OS over 5 yr with NAC before cystectomy.
3. Choosing the right chemo option:
In the neoadjuvant setting, ddMVAC is preferred if patient is fit.
Medically fit cisplatin eligible patients may be treated with 6 cycles of DDMVAC ( VESPER trial)
Another option is 4 cycles of Gemcitabine cisplatin with split dose cisplatin. This is preferable for those with co-morbidities especially where cisplatin eligibility may be questionable e.g CKD with GFR 40-60.
While there appears to be a higher path CR rate with DDMVAC 42% versus 36% GC group.
4. After cystectomy, PDL1 testing will be done. If PDL1 1% or higher, 1 yr nivolumab if no contraindications to immunotherapy. DFS 22 months versus 13 months nivo versus placebo.
5. Side effects of cisplatin: hearing loss, need for hearing aids, neuropathy, kidney damage usually reversible, high risk of emesis and need to take prophylactic nause meds.
Side effects of gemcitabine- abnormal blood counts, fatigue, risk of infection and sepsis. Liver functio abnormality.
5-year analysis of the French phase III VESPER trial showed no improvement in overall survival with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) vs gemcitabine and cisplatin (GC) in the total perioperative (intention-to-treat [ITT]) population of patients with muscle-invasive bladder cancer. Improvement in overall survival with dd-MVAC was observed among patients treated in the neoadjuvant setting, who constituted the majority of the study population.
Reference: VESPER trial update ASCO post
Gem-Cis- Durvalumab-- 2 yr OS 82% versus 75% without durva. Path CR with durva 37% versus 27%
Cisplatin ineligible
Other options:
1. Neoadjuvant enfortumab: path CR 36%, EFS 2 yr 62%. Pts received 3 cycles of neoadjuvant EV (1.25mg/kg) on Days 1 and 8 of each 3-week cycle followed by RC+PLND and then 6 cycles of adjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3 week cycle starting 8 weeks post-RC. Primary endpoint is pathological CR (pCR) per central pathology review; secondary endpoints include pathological downstaging (pDS) rate per central pathology review, safety and tolerability. Here we present initial results from the neoadjuvant/RC+PLND phase + 30 days post surgery.
2. Neoadjuvant pembrolizumab: PURE -01 trial- 3 courses neoadjuvant pembro then cystectomy. The PURE-01 study tested the activity of preoperative pembrolizumab (pembro) in patients (pts) with muscle-invasive bladder (MIBC), resulting in 38.5% pathologic complete responses (pT0N0). As a result of this study, pembrolizumab is often considered in patients who are cisplatin-ineligible with MIBC
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