Unfavorable Cancer-specific Survival After Neoadjuvant Chemotherapy and Radical Cystectomy in Patients With Bladder Cancer and Squamous Cell Variant: A Multi-institutional Study

Abstract

Background: Non-urothelial carcinoma (UC) malignancies are traditionally considered to yield a more aggressive clinical course and little is known about their response to neoadjuvant therapy. We examined the effect of neoadjuvant chemotherapy (NAC) on a large population of bladder cancer (BCa) patients with histological variant (HV). Methods:We relied on aretrospective, multicentre database including 2,858 patients with BCa, who received radical cystectomy (RC) +/− NAC, between 1990 and 2017. Pure and mixed HVs were grouped into six categories: squamous cell carcinoma (SCC) (n=283, 45%), other subtypes (n=95, 15%), micropapillary (n=85, 14%), adenocarcinoma (n=65, 10%), small-cell (n=54, 8.6%) and sarcomatous (n=47, 7.6%). Kaplan-Meier and Cox regression analyses examined the cancer specific survival (CSS) according to HVs, using pure UC as reference. Logistic regression models examined the odds of clinic-pathological downstaging after NAC according to HV.Results: Overall, we identified2,229 pure UC and 629 BCa with HV at RC. Among neoadjuvant chemotherapy-treated patients (N=450), only patients with SCC (44, 9.8%) were associated with worse CSS (median CSS: 33 vs. 116 months, p<0.001) and higher mortality rates (hazard ratio: 2.1, p=0.03) compared to pure UC (328, 72.9%). Analyses were also confirmed when pure and mixed cases were considered separately. After adjusting for NAC, only SCC showed lower rate of clinical-to-pathological downstaging (odds ratio: 0.4, p=0.03) compared to UC.Conclusions: SCC was the variant histology exhibiting the lowest effect of NAC in terms of activity and CSS. In comparison with pure UC, SCC seems to be insensitive to traditional NAC regimens. MICROABSTRACTLittle is known about the response to neoadjuvant therapy of non-urothelial carcinoma (UC) bladder malignancies. Using a retrospective, multicentre database, we found that squamous-cell Bandini et al.

Molecular Subtypes as a Basis for Stratified Use of Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer—A Narrative Review

“…Interestingly, the finding that luminal-like subtypes are more responsive than basal are in line with what is known on the response of histologic variants of MIBC. Micropapillary tumors are luminal-like [ 69 ] and have been described to have a good response to NAC [ 70 , 71 ], whereas squamous-cell carcinoma of the bladder has a poor response to NAC [ 72 , 73 , 74 , 75 ]. One interpretation of histologic variants is that they represent extreme forms of the various differentiation states of urothelial carcinoma captured by molecular subtypes [ 56 ].…”

Pathological and Survival Outcomes Associated with Variant Histology Bladder Cancers Managed by Cystectomy with or without Neoadjuvant Chemotherapy

“…7,12 In the setting of MIBC, however, reports and opinions conflict regarding the benefit of NAC. 6,11,12,[15][16][17] In a review of 2,018 patients with nonPUC histology from the National Cancer Database Vetterlein et al found that although NAC decreased the frequency of nonorgan confined disease at the time of cystectomy in micropapillary bladder cancer cases, this did not translate into a survival benefit. 15 However, in a series of 82 patients from Memorial Sloan Kettering Cancer Center down staging to pT0 occurred in 45% of patients who received NAC compared to 13% who did not, and patients with pT0 disease had higher OS rates (92% vs 25%) and lower rates of recurrence (21% vs 79%) at 24-month followup.…”

“…8,10,14 In cases with heterogeneous histology comprised of both urothelial and nonurothelial components the limited availability of comparative data and conflicting results of existing studies pose an opportunity to better define the effectiveness of NAC and cystectomy. 6,11,12,[15][16][17] To address this clinical question, we compared chemotherapy response as measured by pathological down staging and survival outcomes among bladder cancers with nonPUC histology treated with either NAC followed by cystectomy or cystectomy alone.…”

Dissecting patterns of care in patients with variant histology of bladder cancer and lymph node invasion

“…Micropapillary morphology in solid malignancies is known to have a distinct propensity for lymphovascular invasion, which can lead to a higher rate of LNI compared with the non-micropapillary histological variants [29,30]. Therefore, these observations suggest the need for further studies involving an accurate analysis of the biological, pathological, and clinical factors of the urothelial and non-urothelial bladder cancer variants 16 (88.9) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (11.1) to define the best multidisciplinary (surgery, radiation therapy, chemotherapy, and innovative treatment strategies) approach for each histological subtype, with a particular emphasis on immunotherapy and targeted therapies [31][32][33][34].…”