Table 7. Studies on multiple variant histologies reporting outcomes with either neoadjuvant chemotherapy or upfront radical cystectomy.
| Author (year) | Pathologic complete response | Pathologic downstaging | Median follow up after cystectomy | Survival outcomes after cystectomy | Major independent factor(s) other than histologic phenotype affecting response/outcomes analyzed | Comments |
|---|---|---|---|---|---|---|
| Kaimakliotis (5) (2016), n=919 (VH n=181) | Patients who received either regimen had higher incidence of pCR (29% vs. 8%, P=0.002) compared to those who did not. The pCR to NAC in squamous and glandular differentiation was similar to conventional UC (pCR 29 vs. 22%; P=0.443 | There was higher incidence of pathologic downstaging (52% vs. 14%; P<0.001), comparing those who received either regimen as NAC versus those who did not. Pathological downstaging to NAC in squamous and glandular differentiation was similar to conventional UC (52% vs. 43%; P=0.370) | 77 months | VH was not associated with an increased risk of mortality. Use of either MVAC or GC as NAC was associated with decreased the risk of mortality in the cox proportional hazards regression model | Regimen used had no impact on pathologic response as both MVAC and GC resulted in improved pathologic response rates. Comparing MVAC to GC, either resulted in decreased mortality in VH subgroup studied. Only MVAC reached statistical significance | – |
| Patients received either MVAC or GC as NAC regimen | ||||||
| Shen (8) (2015), n=90 (VH n=90) | pCR reported as 23.9% vs. 4.5% comparing recipients of NAC vs. recipients of upfront RC | Rate of downstaging to < pT2 was 32.6% vs. 9%. Comparing recipients of NAC vs. recipients of upfront RC | Notable changes both in percent variant differentiation and mitotic rate occurred with NAC use from Bx/TUR to RC but not in non-NAC treated tumors. Neither change was predictive of response to NAC | The aim of this study was to describe changes in bladder tumors during NAC use and to identify features at Bx/TUR that may predict response | ||
| Hajiran (14) (2021), n=768 (VH n=358) | pCR was achieved in 23% of conventional UC cases, 30% of UC with VH cases and 18% of UC with divergent squamous or glandular differentiation cases (P=0.30) | Partial response was achieved in 46% of conventional UC cases, 41% of UC with VH cases and 37% of UC with divergent squamous or glandular differentiation cases (P=0.40) | 21 months | Conventional UC cases had OS benefit (HR 0.71, 95% CI: 0.51–0.98, P=0.0013) with NAC. UC with VH cases has CSS benefit (HR 0.55, 95% CI: 0.30–0.99, P=0.0495) with NAC. UC with divergent glandular or squamous differentiation cases did not experience any survival benefit with NAC prior to RC | Rates of complete and partial pathologic response were similar between the three groups | |
| NAC Treatment response stratified into three groups1. Conventional UC2. UC with VH3. UC with divergent glandular or squamous differentiation | ||||||
| Soave (19) (2017), n=188 (VH n=47) | 25 months | UC with VH had worse survival outcomes compared to UC with divergent squamous differentiation. UC with VH and presence of circulating tumor cells (CTC) were associated with reduced RFS and CSS (P≤0.016) | In multivariable analysis, presence of CTC, not variant histology, was an independent predictor for recurrence of disease (HR 3.45; P≤0.001) and CSS (HR 2.62; P=0.002) | The primary aim of this study was to determine the effect of circulating tumor cells (CTC) on survival outcomes of in patients with VH after RC | ||
| Patients with UC treated with RC without NAC | ||||||
| Soave (16) (2015), n=485 (VH n=96) | 45 months | VH was associated with inferior CSS (P≤0.02) and disease recurrence (P=0.002). | Comparing survival outcomes based on extent of VH i.e., ≥70% or <70%, there was no statically significant difference between the two groups. Age, advanced tumor stage, lymph node involvement and a positive soft tissue margin were all associated with worse survival outcomes | |||
| Moschini (25) (2017), n=338 (VH n=338) | 6.5 years | On multivariable analysis, patients with a predominant VH had inferior survival outcomes compared to conventional UC (P<0.01). On multivariable cox regression analysis predicting recurrence, cancer specific mortality and overall mortality, there were no difference between mixed variant and conventional UC (all P>0.1) | Only the presence of a predominant VH was associated with inferior survival outcomes after RC compared the conventional UC. Same was not true for UC with mixed VH cases which had similar survival outcomes with conventional UC cases | |||
| Patients with non-metastatic UC treated with RC were stratified in three groups:1. UC with mixed VH cases2. UC with a predominant VH (micropapillary or small cell) cases3. Conventional UC cases | ||||||
| Martini (26) (2021), n=2,422 (VH=528) | Relative to conventional UC, patients with VH had higher rates of recurrence with RFS 30% vs. 51%; P<0.001 and shorter median time to disease recurrence (88 vs. 123 months; P<0.01) | The study concluded by Study recommending longer oncologic surveillance time for VH UC | ||||
| Sefik (32) (2018), n=146 (VH n=23) | No significant difference in survival was observed between VH and conventional UC | |||||
| Xylinas (34) (2013), n=1,983 (VH n=488) | 55 months | In univariable analysis, patients with conventional UC and squamous differentiation had similar risk for disease recurrence and cancer-specific mortality. UC with VH had significantly higher risk for disease recurrence and cancer specific mortality on univariable but not multivariable analysis | ||||
| Takemoto (35) (2020), n=102 (VH n=26) | 39.5 months | VH of UC was associated with significantly worse survival compared to conventional UC in RFS (P=0.018) and CSS (P=0.036) | ||||
| Naspro (37) (2021), n=525 (VH n=131) | 31 months | Presence of VH was an independent risk factor for cancer-specific mortality (P=0.001) with significantly higher risk for recurrence, cancer-specific mortality and overall mortality (all P ≤0.001) | ||||
| Stroman (39), n=403 (VH n=73) | 45 months | VH, specifically squamous differentiation was associated with worse survival outcomes | ||||
| Komina (41) (2021), n=185 (VH n=58) | 28.9 months | On multivariable analysis, positive soft tissue margin and lymphovascular invasion were associated with worse RFS and OS | ||||
| Marks (42) (2019), n=138 (VH n=96) | 45 months | Although VH was not associated with increased incidence of lymph node involvement, patients with positive lymph nodes or extra nodal extension undergoing RC had worse survival outcomes |
UC, urothelial carcinoma; VH, variant histology; NAC, neoadjuvant chemotherapy; pCR, pathologic complete response; RC, radical cystectomy; CSS, cancer specific survival; OS, overall survival; RFS, recurrence free survival; MVAC, methotrexate-vinblastine-doxorubicin-cisplatin chemotherapy; GC, gemcitabine-cisplatin chemotherapy; Bx/TUR, biopsy/transurethral resection; CTC, circulating tumor cells.