Bladder and urothelial cancer

Spectrum of disease encountered by medical oncologist

1.  Non muscle invasive bladder cancer

2. Muscle invasive non metastatic

3. Locally advanced or Metastatic bladder cancer

Why is high grade T1 disease concerning?

Within 5 yrs, 9% could die of bladder cancer, 19% has progressed to MIBC and 51 % has recurred.

Restaging is the standard of care since upto 30% are underdiagnosed at the initial cystoscopy.

What are the 5 yr survival data?

NMIBC- 88%

MIBC- 50-60%

Locally advanced 40%

Stage 4-15%

Cystectomy is the best option for histologically variant T1 bladder ca ( squamous, sarcomatoid, NEC):  radical cystectomy compared to bladder preservation treatments (TURBT, intravesical therapies, radiation) for NMIBC with sarcomatoid, squamous, glandular, and neuroendocrine variants (Dursun et al., PMID 35351370). However, radical cystectomy was not associated with survival benefit compared to bladder preservation for NMIBC with micropapillary variant

Perioperative therapy MIBC

1. Upper tract urothelial ca: POUT trial- Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. ( T2 or higher, any N+) Lancet March 2020

2. Neoadjuvant GC for upper tract: path CR 14% phase II Wesley Yip ASCO GU 22

2 yr PFS and OS 78 and 93%. 5 yr OS was 79%

Those who attained path CR PFS 91% and OS 100% in 2 yr

Adjuvant nivolumab Checkmate 274 improves DFS to 20 months instead of 10 months in PDL1 > 1%

Neoadjuvant cisplatin based chemo in bladder ca: meta-analysis shows 5 yr OS and DFS benefit of 5% and 9% resepectively without compromising QOL.

median OS 77 months versus 46 months for MVAC versus placebo.

If giving NAC in bladder ca, how soon should you start? Less than 8 weeks to prevent upstaging

Choice of chemo for NAC: ddMVAC with better PFS and path CR rates compared to GC ( vesper trial). However a full 6 cycles was used in this trial rather than 3-4 cycles as before.

Metastatic bladder cancer

Predictors of worse outcome in MBC: non nodal mets and ECOG 2 or higher

Gemcitabine carboplatin or cisplatin first line followed by avelumab maintenance: Median OS 11 months ( same as gem cisplatin when compared head to head) without maintenance avelumab

With avelumab: Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69;

Pembro first line in platinum ineligible: Pembrolizumab, nivolumab, and avelumab are approved for the treatment of locally advanced or metastatic urothelial cell carcinoma that has progressed during or after platinum-based chemotherapy or that has progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy, regardless of PD-L1 expression levels

Enfortumab pembrolizumab:KEYNOTE-869

 confirmed ORR in 121 patients was 68% (95% CI: 59, 76), including 12% with complete responses. The median DoR for the dose escalation cohort + Cohort A was 22 months (range: 1+ to 46+) and for Cohort K was not reached (range: 1 to 24+)

How to counsel patients about side effects of enfortumab?

The most common adverse reactions (>20%), including laboratory abnormalities, were increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, increased lipase, decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin