Do mixed histological features affect survival benefit from neoadjuvant platinum‐based combination chemotherapy in patients with locally advanced bladder cancer? A secondary analysis of Southwest Oncology Group‐Directed Intergroup Study (S8710)

Abstract

and for patients with mixed tumours, with adjustment for age and clinical stage. RESULTS• There was evidence of a survival benefit from chemotherapy in patients with mixed tumours (hazard ratio 0.46; 95% CI 0.25-0.87; P = 0.02). Patients with pure UC had improved survival on the chemotherapy arm but the survival benefit was not statistically significant (hazard ratio 0.90; 95% CI 0.67-1.21; P = 0.48).• There was marginal evidence that the survival benefit of chemotherapy in patients with mixed tumours was greater than it was for patients with pure UC (interaction P = 0.09). CONCLUSION• Presence of squamous or glandular differentiation in locally advanced UC of the bladder does not confer resistance to MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy. KEYWORDS urothelial carcinoma, mixed histological features, neoadjuvant chemotherapyWhat's known on the subject? and What does the study add?In a meta-analysis of randomized trials, neoadjuvant platinum-based combination chemotherapy administered before definitive local treatment improved survival of patients with muscle-invasive bladder cancer compared with definitive local treatment alone. However, it was not known whether chemotherapy was equally effective for pure urothelial carcinoma versus urothelial carcinoma with mixed histological features, such as squamous or glandular differentiation.To address this question we performed a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy versus cystectomy alone for treatment of locally advanced urothelial cancer of the bladder. Our findings suggest that presence of squamous or glandular differentiation does not confer resistance to combination chemotherapy with MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.Study Type -Therapy (RCT) Level of Evidence 1b OBJECTIVE• To determine whether the effect of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) on the survival of patients with locally advanced urothelial carcinoma (UC) of the bladder treated with radical cystectomy varies with the presence of nonurothelial components in the tumour. PATIENTS AND METHODS• This is a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant MVAC followed by cystectomy versus cystectomy alone for treatment of locally advanced UC of the bladder.• For the purpose of these analyses, tumours were classified based on the presence of non-urothelial components as either pure UC ( n = 236) or mixed tumours ( n = 59). Non-urothelial components included squamous and glandular differentiation.• Cox regression models were used to estimate the effect of neoadjuvant MVAC on all-cause mortality for patients with pure UC

1593 Comparative Outcomes of Pure Squamous Cell Carcinoma and Urothelial Carcinoma With Squamous Differentiation in Patients Treated With Radical Cystectomy

“…Conversely, patients with positive soft tissue margins and SqD may still benefit from platinum based chemotherapy, which has proven effective for urothelial carcinoma with mixed features, and suggests possible differences in molecular pathways for metastases in pure SCC. 20 Our findings must be interpreted in the context of the study design. This study is retrospective, and our results are limited by unmeasured factors affecting selection into treatment and confounding the associations between tumor characteristics and outcomes.…”

Does Squamous Differentiation Portend Worse Outcomes in Urothelial Bladder Cancer?

“…Similarly, Kastritis et al found that when treating advanced or metastatic urothelial carcinoma with a platinum-based chemotherapy regimen, SQD and NV bladder cancer exhibited similar responsiveness 16 . Lastly, in a secondary analysis of the SWOG S8710 clinical trial using neoadjuvant MVAC (methotrexate, vincristine, doxorubicin, and cisplatin), SQD demonstrated nonstatistically significant (p=0.09) improved survival benefit compared to NV in locally advanced urothelial carcinoma 14 . In our cohort, patients receiving neoadjuvant chemotherapy responded at similar rates although we are significantly underpowered to fully evaluate this.…”

“…While recent studies have found certain variants such as micropapillary and plasmacytoid to act more aggressively, SQD has been historically described to act similarly to NV histology 5,11,14,15,18,19 . However, much of the SQD literature draws on older cohorts.…”

“…Although SQD was previously shown to be associated with higher pathologic staging and increased risk of local recurrence, when accounting for stage, SQD does not alter overall survival (OS) or disease-specific survival (DSS) 7,8,[11][12][13] . Furthermore, there is evidence suggesting that SQD may be equally sensitive to chemotherapy as non-variant (NV) urothelial bladder cancer 10,12,[14][15][16][17] .…”

Quelle chimiothérapie périopératoire pour les tumeurs de vessie infiltrant le muscle ?

“…Les variants les plus fréquents sont les carcinomes urothéliaux avec inflexions épidermoïdes ou adénocarcinomateuses. Dans l'essai du SWOG, la présence de ces variants a même été décrite comme une variable plutôt favorable pour l'obtention d'une RCP [16]. Les carcinomes non urothéliaux (10 % des cancers de la vessie) comprennent les adénocarcinomes, dont les carcinomes de l'ouraque, les carcinomes épidermoïdes, les carcinomes neuroendocrines à petites cellules et les sarcomes primitifs de la vessie.…”