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The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: A systematic review

The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant... ARAB JOURNAL OF UROLOGY 2022, VOL. 20, NO. 1, 1–13 https://doi.org/10.1080/2090598X.2021.1994230 REVIEW ONCOLOGY/RECONSTRUCTION The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: A systematic review a b b a a Mario Alvarez-Maestro , Francesco Chierigo , Guglielmo Mantica , J. M. Quesada-Olarte , D. M. Carrion , a a a a Juan Gomez-Rivas , Alvaro Pinto-Marin , Alfredo Aguilera Bazan and Luis Martinez-Piñeiro a b Department of Urology, Hospital Universitario La Paz, Madrid, Spain; Department of Urology, Policlinico San Martino Hospital, University of Genova, Genoa, Italy ABSTRACT ARTICLE HISTORY Received 23 January 2021 Objective: To systematically review the evidence about the effect of neoadjuvant chemother- Accepted 20 April 2021 apy (NAC) for muscle-invasive bladder cancer (MIBC) with pure urothelial carcinoma (pUC) in radical cystectomy (RC) candidates affected by variant histology (VH) bladder cancer. KEYWORDS Methods: A review of the current literature was conducted through the Medline and National Bladder cancer; neoadjuvant Center for Biotechnology Information (NCBI) PubMed, Scopus databases in May 2020. The chemotherapy; systematic updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were review; radical cystectomy; followed for this systematic review. Keywords used were ‘bladder cancer’, ‘bladder carcinoma’, variant histology urothelial cancer ‘bladder tumour’ and ‘bladder cancer variants’ and ‘neoadjuvant chemotherapy’. Only original articles in English published after 2000 and reporting oncological outcomes a series of more than five patients with VH were included. We excluded series in which the oncological out- comes of patients with pUC and VH were undistinguishable. Results: The literature search identified 2231 articles. A total of 51 full-text articles were assessed for eligibility, with 17 eventually considered for systematic review, for a cohort of 450,367 patients, of which 5010 underwent NAC + RC. The median age at initial diagnosis ranged from 61 to 71 years. Most patients received cisplatin-gemcitabine, methotrexate- vinblastine-adriamycin-cisplatin, or carboplatin-based chemotherapy. Only one study reported results of neoadjuvant immunotherapy. The median follow-up ranged from 1 to 120 months. The results showed that squamous cell carcinoma (SCC) is less sensitive to NAC than pUC and that SCC predicts poorer prognosis. NAC was found to be a valid approach in treating small cell carcinoma and may have potential benefit in micropapillary carcinoma. Conclusions: NAC showed the best oncological outcomes in small cell variants and micro- papillary carcinoma, while NAC survival benefit for SCC and adenocarcinoma variants needs further studies. Drawing definite considerations on the efficacy of NAC in VH is complicated due to the heterogeneity of present literature. Present results need to be confirmed in randomised controlled trials. Introduction common variants [3,4]. A population-based study con- ducted on Surveillance, Epidemiology and End Results Bladder cancer is the most common neoplasm of the (SEER) data, reported an annual incidence rate (calcu- urinary tract and worldwide the 11th most diagnosed lated according to the total USA population) for SCC of cancer [1]. In most cases, bladder cancer is a pure 903 cases/year, 450 for adenocarcinoma and 447 for urothelial carcinoma (pUC) but, in around 10–30% of neuroendocrine tumours, while pUC was >50-times patients, bladder cancer presents with a non-pure UC more common than any VH [5]. The impact of cisplatin- (npUC) or with pure variant histology (VH) without based neoadjuvant chemotherapy (NAC) before RC for a UC component. Unlike pUC, the true prevalence, high-grade muscle-invasive bladder cancer (MIBC) has treatment options, and prognosis of these VHs are been well established, with meta-analyses of prospec- not well characterised. In an institutional study asses- tive trials showing a 5–7% absolute overall survival sing the incidence of VH in patients treated with radi- (OS) [6–11]. No randomised controlled trials (RCTs) cal cystectomy (RC), 10.2% were found with squamous have focussed on the rarer and more aggressive VH cell carcinoma (SCC), 8.3% with micropapillary carci- subtypes of UC of the bladder. Prognosis is diverse for noma, 2.2% with glandular, 2.0% with sarcomatoid VH and there is a lack of evidence on the ideal treat- variant, 1.8% with small cell, 0.9% with lymphoepithe- ment approach. Today, RC is still the ‘gold standard’ for lial, 3.2% with mixed variants, and 3.1% with other both pUC MIBC and MIBC with VH [1]. In order to variants [2]. These findings are consistent with other improve the low 5-year survival provided by RC; cispla- two institutional studies, in which SCC, sarcomatoid, tin-based NAC has been used over the last three glandular and small cell were found to be the most CONTACT Mario Alvarez-Maestro malvarezmaestro@hotmail.com Department of Urology, Hospital Universitario La Paz, Madrid, Spain © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 M. ALVAREZ-MAESTRO ET AL. decades. Nevertheless, the literature is scant regarding of both pUC and npUC patients in which the oncolo- the impact of different rare variants on the response to gical outcomes of patients with pUC and of those with NAC, while npUC histology has been found to have npUC could not be distinguished. a different response to palliative systemic therapies [9]. Some of the few available studies regarding NAC Data extraction design found a survival benefit in patients with neuroendo- crine tumours and in those with squamous and gland- The overall risk of bias and Levels of Evidence (LoE) ular differentiation [12]. On the contrary, the presence were assessed by the three reviewers using the Risk Of of bladder cancer VHs was associated with lower rates Bias In Non-randomised Studies – of Interventions of response to NAC in other studies [13,14]. (ROBINS-I) tool recommended by Cochrane and the Considering this, the aim of the present systematic Oxford Centre for Evidence-Based Medicine (OCEBM) review was to provide the most recent and updated criteria [17,18]. Variables that were recorded, when evidence about the effect of NAC in RC candidates with possible, included: variables related to the publication VH bladder cancer. (year, country, design of the study); demographics (sample size, age, gender), histology at transurethral resection of bladder tumour (TURBT) or RC, TNM stage, Methods NAC regimens given, type of loco-regional therapy, follow-up, oncological outcomes, and toxicity data Literature search strategy with the complications/toxicity classification used. A review of the current literature was conducted through the Medline and National Center for Statistical analysis Biotechnology Information (NCBI) PubMed, Scopus databases in May 2020. The updated Preferred Data were entered into a Microsoft Excel (version 14.0) Reporting Items for Systematic Reviews and Meta- database and then transferred to Sofastat TM 1.4.6 for Analyses (PRISMA) guidelines were followed for this Windows. Descriptive statistics were calculated for all systematic review [15]. demographic, treatment, clinical and follow-up vari- Keywords used were: ‘bladder cancer’, ‘bladder ables, and reported as median (interquartile range carcinoma’, ‘bladder tumour’ and ‘bladder cancer [IQR]) or as a proportion with percentage. variants’. We used the previous keywords as our primary search string, which combine established Results Medical Subject Headings (MeSH) terms for ‘neoad- juvant chemotherapy’ with the highly sensitive The PRISMA flow chart of the systematic review is Cochrane search strategy. The reference lists of the presented in Figure 1. We identified 2231 articles retrieved reviews were also checked and cross- from the Scopus and PubMed database searches. referenced [16]. EndNote removed 999 duplications, 947 articles were The searches were performed independently by discarded according to title, non-English language, two researchers (F.C. and G.M.), and any disagreement and type of article (case reports, letters, editorials, resolved by a third independent researcher (M.A.M.). reviews, etc.), and further 234 after reading the The initial screening was done on the base of titles and abstract. Overall, 51 full-text articles were assessed for abstracts. eligibility: eight articles were excluded because they considered less than five patients with VH undergoing NAC, 15 because the articles did not report oncological Inclusion and exclusion criteria results, and 11 because oncological results were not All papers published after the year 2000, concerning divided by histological type. studies conducted on humans for NAC for bladder A summary of the variables is shown in Table 1. cancer were considered for the review. Duplications Of the 17 articles included in the present review, 13 were excluded using the dedicated tool on EndNote were retrospective studies and three were clinical software. Only original articles (randomised controlled trials (Table 1) [13,14,19–33]. The median age at trials, cohort studies, case-control studies) for series of initial diagnosis ranged from 61 to 71 years and more than five patients were included. Other publica- males greatly outnumbered females. The cohort of tions such as reviews, commentaries, editorials, and patients we considered comprised 450,367 patients, letters to the editor were excluded. The most recent of which 5010 underwent NAC and RC. Due to the publication was considered if several studies evaluated vast heterogeneity in the studies, it was quite diffi - the same patient cohort. Only studies published in cult to understand how many patients with npUC English were considered. Further, only studies report- underwent NAC + RC. The clinical stage of most of ing oncological outcomes of patients with rare HVs the population studied was cT2N0. Most patients were included in the review. We also excluded series received cisplatin-gemcitabine (CG), methotrexate- ARAB JOURNAL OF UROLOGY 3 Records identified through database searching (n = 2231 ) Records after duplicates removed (n = 1232) Records excluded based on title, non‐ Records screened English language and type of article (n =1232) (n = 947), and based on abstracts (n=234) Full‐text articles excluded, with reasons (n = 31): Full‐text articles assessed ‐Less than 5 NCT pts with variant histology for eligibility (n=8) (n = 51) ‐Non‐oncological results (n=15) ‐Oncological results not divided by histology (n=11) Studies included in qualitative synthesis (n = 17 ) Figure 1. Flow diagram. vinblastine-adriamycin-cisplatin (MVAC) or carbopla- The results are consistent with those by Matulay tin-based chemotherapy, with only one reporting et al. [20], who, still using the NCBD, showed that the results of neoadjuvant immunotherapy. median OS for patients with SCC who received RC Unfortunately, five of 17 articles did not report the alone was 25.4 months compared to 34.0 months NAC regimens undergone and only one reported with NAC, although not statistically significant. NAC-related toxicities. The median follow-up ranged The NCDB was queried once again by Stensland from 1 to 120 months, averaging at ~40 months. et al. [21] for cases of localised, muscle-invasive pure Oncological results were also reported in quite dif- squamous cell bladder cancer, classified as clinical ferent ways, mainly: downstaging after NAC, recur- stage T2/3N0M0. In this study, the unweighted median rence-free survival (RFS), cancer-specific survival survival was 46 months for RC alone, and 21 months (CSS), OS, recurrence rate, and mortality rate (MR) for NAC + RC. However, in the weighted multivariate (Table 2) [13,14,19–33]. Cox model, compared to RC alone, NAC did not sig- nificantly differ with regard to OS. One major limitation of these three studies is that Squamous cell carcinoma (SCC) the NCDB lacks specific data on chemotherapy: the type, duration, and dose of chemotherapy cannot be Three studies focussed on SCC. Using data from the analysed, so NAC is probably a heterogeneous group National Cancer Database (NCDB), Dotson et al. [19] comprising multiple types of chemotherapeutic evaluated the management and survival of patients regimens. with invasive SCC treated with or without NAC. A study from Japan also tried to investigate the Although more patients were down-staged to non- efficacy of cisplatin-based chemotherapy (MVAC or invasive disease (pT < 2) in the NAC group, the 2-year CG) and prognosis of patients with UC with or without OS was not statistically significantly different, being squamous differentiation of the bladder. In this study, 54.8% for RC alone and 45.7% for NAC + RC. none of the patients with SCC achieved pathological Included Eligibility Screening Identification 4 M. ALVAREZ-MAESTRO ET AL. Table 1. Summary of study design and pre-therapy patients’ characteristics of the studies considered for review. Study Sample Authors design size Age, years Gender Histology TNM Stage Notes Bandini R 950 68 NA §206 pUC cT stage §Histology at TURBT et al. (242 36 npUC cT2 = 59.9% [27] NAC) cT3–4 = 37.6% Unknown = 2.5% pT stage pT0 = 32.6% pTa/pTis = 8.3% pT1 = 6.6% pT2 = 17.4% pT3 = 26.9% pT4 = 8.3% pN Stage pNx = 1.2% pN0 = 81.4% pN1 = 8.3% pN2 = 8.7% pN3 = 0.4% Bandini R 285 68 2331 Male **UC = 78% **cT stage *Histology at RC; **% of pts et al. (450 527 SCC = 9,9% <cT2 = 17.7% undergoing NAC + RC is not [29] NAC) Female MPUC = 3% cT2 = 57.1% available; ***when considering ADC = 2,3% cT3-4 = 12.5% npUC, % include both pure and Small cell = 1,9% Unknown = 12.7% combined VH Sarcoma = 1,6% cN stage Other = 3,3%*** cN0 = 43.6% cN1 = 5.4% cN2 = 3.6% cN3 = 0.4% cNx = 16.2% Unknown = 30.9% pTN stage <pT2N0M0 = 14% pT0N0M0: 3.8% pT2N0M0 = 12.4% pT3-T4N0M0 = 27.5% pTanyN +M0 = 37.3% pTanyNx = 4.9% Brimo R 165 65 119 Male UC = 76% pT stage et al. 46 npUC = 24% pT0 = 16% [28] Female pTis = 14% pTa = 2% pT1 = 9% pT2 = 17% pT3 = 26% pT4 = 16%; pN stage N0 = 68% N1 = 13% N2 = 15% N3 = 4% Dotson R 671 61 NA SCC cT stage et al. (48 cT2 = 75% [19] NAC) cT3 = 25% pT stage: <pT2 = 10.4% pT2 = 16.7% pT3 = 50% pT4 = 16.7% Unknown = 6.3% pN+ = 18.7% Kamat R 100 66 21 Male MPUC cT stage et al. (23 3 Tis = 4.4% [23] NAC) Female Ta = 0% T1 = 39.1% T2 = 30.4% T3 = 13.0% T4a = 13% pT stage pT0 = 39.1% pTis = 17.4% pT1 = 4.4% pT2 = 4.4% pT3 = 17.4% pT4 = 4.4% N+ = 13% (Continued) ARAB JOURNAL OF UROLOGY 5 Table 1. (Continued). Study Sample Authors design size Age, years Gender Histology TNM Stage Notes Lin et al. R 195 66 *7 Male pUC = 161 *cT stage *N° referring to pts with npUC [30] (37 5 npUC = 34 cT2 = 58% undergoing NC NAC) Female cT3 = 25% cT4 = 17% Lynch R 172 67 41 Male SC only = 22 cT stage et al. (48 7 >50% SC = 18 ≤ cT1N0 = 1 [26] NAC) Female <50% SC = 8 cT2N0 = 30 cT3-4aN0 = 17 Matulay R 260 NA *UC = 3896 cT2-4N0M0 * N° referring to NAC + RC patients et al. (75 SCC = 75 [20] NAC) Meeks R 44 71 26 Male MPUC NA et al. (29 18 [24] NAC) Female Minato R 38 66 29 Male UC = 29 UC et al. 9 SCC = 9 T3 = 93.6% [22] Female T4 = 3.4% SCC T3 = 88.9% T4 = 11.1% Necchi P-II 114 66 99 Male pUC = 80 cT stage et al. CT (111 15 npUC = 34 T2 = 54% [33] NAC) Female 33% SCC T3 = 44% 17% nested T4 = 3.6% 12% MPUC 9% LEL, 6% sarcomatoid 6% ADC+SCC 3% ADC 3% small cell 3% plasmacytoid 3% spindle cell 3% clear cell 3% SCC+SC Pokuri R 50 67,5 41 Male pUC = 52% Clinical stage et al. 9 npUC = 48% cT2N0 = 62% [14] Female cT3N0 = 22% cT4N0 = 16% Scosyrev CT 307 VH VH – NAC pUC = 236 VH *patient % relative to those who et al. (124 NAC + + RC SCC = 37 cT3–cT4a = 59% received NAC + RT [13] NAC) RC = 60 69% ADC = 20 Male SCC+ADC = 2 31% Other = 2 Female VH VH – RC RC = 65 85% Male 15% Female pUC pUC – pUC NAC + NAC + cT3–cT4a = 59%* RC = 63 RC 86% Male 14% Female pUC pUC + RC RC = 62 79% Male 21% Female Siefker- P-II 65 62,5 50 Male pUC = 57% cT stage of bladder/ *VH ≤50% of the specimen Radtke CT 15 VH = 43% urethra tumor et al. Female (MPUC 46% of VH)* (n = 60) [31] cT2 = 37 cT3b = 18 cT4a = 5 Tumor in the renal pelvis or ureter = 5 Stensland R 828 63,5 29 Male SCC cT stage et al. (53 16 T2 = 79.2% [21] NAC) Female T3 = 20.8% (Continued) 6 M. ALVAREZ-MAESTRO ET AL. Table 1. (Continued). Study Sample Authors design size Age, years Gender Histology TNM Stage Notes Sui et al. R 439188 pUC = 71,1 pUC *UC = 3052 MPUC * N° referring to pts undergoing [25] (3083 Male MPUC = 31 cT stage NAC + RC NAC) 75.4% Tx 17.4% Female T0 = 0% 24.6% Tis = 5.2% T1 = 29.8% T2 = 35.4% T3 = 7.1% T4 = 5.1% cN stage N0 = 70% N+ = 9.1% Nx = 20.9% cM stage M0 = 95.3% M1 = 4.7% MPUC = 69.9 MPUC UC Male cT stage 78.3% Tx 16.5% Female T0 0.3% 21.7% Tis 47.2% T2 11.5% T3 1.6% T4 1.8% cN stage N0 77.4% N + 1.8% Nx 20.8% cM stage M0 98.1% M1 1.9% Vetterlein R 2018 66,7 Male MPUC = 7.6% cT2N0 = 65.1% et al. (369 62.4% sarcomatoid = 15.1% ≥cT2 and/or [32] NAC) Female SCC = 40.1% cN1 = 34.9% 37.4% ADC = 17.7% NE = 13.3% other = 6.1% ADC: adenocarcinoma; NE: neuroendocrine; P-II CT: phase II clinical trial; R: retrospective; SC: small-cell. complete response (pCR) to NAC and the proportion of year OS rate of 63% in patients treated with NAC + down-staging was lower in patients with SCC than in RC, which was not significantly different from what ones with pUC [22]. The median follow-up was 16 and was observed for the patients treated with upfront 48 months in patients with SCC and pUC, respectively. RC, who had a 5-year OS rate of 71%. Interestingly, After RC, recurrence developed in 88.9% and 48.3% of patients who had non-MIBC (NMIBC), delaying sur- the patients with SCC and pUC, respectively; and 77.8% gery for neoadjuvant therapy demonstrated a trend and 48.3% died in the SCC and pUC groups, respectively. toward a decreased median survival and 5-year sur- From these results, it appears that SCC is less sensi- vival rate compared to upfront surgery. tive to NAC than pUC, and that SCC predicts poorer Another study reported that the rates of recur- prognosis. However, there is a need for larger, prospec- rence (33% vs 62%), cancer-specific mortality (66% tive investigations, with design confronting different vs 57%) and overall mortality (71% vs 84%) were NAC regiments in patients with SCC. not different at 2 years between patients who did or did not receive NAC. However, down-staging to pT0 occurred in 45% of patients receiving NAC, Micropapillary carcinoma compared with 13% of those who underwent upfront RC (P = 0.049). Despite micropapillary his- We identified three studies focussing on micropapillary tology, those with pT0 had improved outcomes carcinoma. Kamat et al. [23] retrospectively reviewed after RC, with a lower rate of recurrence, lower data of 100 patients with micropapillary carcinoma, 23 bladder cancer-specific mortality and longer time of them undergoing NAC + RC. They observed a 5‒ ARAB JOURNAL OF UROLOGY 7 to death. Therefore, the authors [24] concluded npUC (P = 0.048) and pUC (P < 0.001), as compared that patients with the micropapillary variant of UC to those in each group who did not receive NAC. should not be excluded from consideration However, NAC was not a significant predictor of OS for NAC. for patients with npUC in a Cox multivariate model Sui et al. [25] analysed data of from the NCBD, in (P = 0.54) and, among all patients treated with NAC, which 94 patients with ≥cT2 disease were identified. In mixed histology was found to be a predictor of poorer this study, there was not a statistically significant dif- survival. ference in median OS between patients who received In addition, Pokuri et al. [14] found that the odds of NAC and those who did not. a pT0 response for pUC were approximately 11-times greater relative to cancers with VH features or mixed tumours (OR 0.09, 95% CI 0.021–0.380; P = 0.001), Small cell carcinoma including squamous, glandular differentiation, small cell, micropapillary, sarcomatoid, nested component, Lynch et al. [26] identified 125 patients with small cell lymphoepithelioma-like (LEL), and plasmacytoid UC with a clinical stage ≤cT4aN0M0. Of these, 95 were variants. surgical candidates: 48 received NAC and 47 under- A secondary analysis of the Southwest Oncology went upfront RC. Neoadjuvant treatment was asso- Group (SWOG)-directed intergroup randomised trial ciated with improved OS and CSS compared with S8710 of neoadjuvant MVAC followed by RC vs RC initial RC (median OS: 159.5 vs 18.3 months, alone for treatment of locally advanced UC of the P < 0.001; 5-year CSS: 79% vs 20%, P < 0.001). NAC bladder gave evidence of a survival benefit from che- resulted in pathological downstaging to ≤pT1N0 in motherapy in patients with mixed tumours (HR 0.46, 62% of tumours compared with only 9% treated with 95% CI 0.25–0.87; P = 0.02). Moreover, there was mar- initial RC. Although limited by a small sample size with ginal evidence that the survival benefit of NAC in a retrospective analysis, and this being the only article patients with mixed tumours was greater than it was dealing solely with small cell carcinoma, these data for patients with pUC. These analyses also showed that suggest NAC as a valid approach in treating small cell the estimated improvement in 5-year survival asso- carcinoma of the bladder. ciated with MVAC was much greater in magnitude among patients with npUC than among patients with Articles studying more than one npUC histology pUC [13]. A phase II clinical trial of sequential NAC with ifos- The other nine studies we included in the present famide, doxorubicin, and gemcitabine, followed by review considered npUC without discriminating for cisplatin, gemcitabine, and ifosfamide showed that histological type or considered many histological the presence of VH was associated with an inferior variants. 5-year CSS of 50% as compared to 83% for pUC (log- In 2019, Bandini et al. [27], in a study aimed at rank P = 0.02). In this series, the presence of micropa- modelling 1-year RFS after NAC + RC in patients with pillary histology was associated with a 5-year OS and cT2–4N0M0 bladder cancer, showed that npUC was CSS of 54%. A pUC histology was also a significant not a predictor of recurrence after RC at univariable factor to disease-specific survival (relative risk 0.35 for Cox regression model analysis. On the contrary, UC vs mixed, P = 0.03). This clinical trial was the only a multicentric study which also investigated prognos- study included in our review to report NAC-related tic pathological factors in RC after NAC showed that VH toxicities. There was only one death due pneumonia was a predictor of recurrence, but not of cancer-related during neutropenia. In all, 6% of patients had Grade 4 death [28]. toxicities (myocardial infarction, platelet transfusion, In 2020, a multi-institutional study aimed to exam- and vomiting), while the most frequent Grade 3 toxi- ine the effect of NAC on bladder cancer with different cities were infection (38%), febrile neutropenia (22%), histological variants [29]. Of the 450 NAC-treated and mucositis 18%, and platelet transfusion (12%) [31]. patients, only patients with SCC had had worse CSS In 2017, Vetterlein et al. [32] assessed the effect of (median CSS, 33 vs 116 months; P < 0.001) and higher NAC on OS after RC in patients with HVs, finding an OS mortality rates (hazard ratio [HR] 2.1; P = 0.03) com- benefit for NAC only in patients with neuroendocrine pared with those with pUC. After adjusting for NAC, tumours (HR 0.49, 95% CI 0.33–0.74; P = 0.001). For only SCC showed a lower rate of clinical-to- other HVs, even if NAC decreased the frequency of non- pathological downstaging (odds ratio [OR] 0.4; organ confined disease at the time of RC, this did not P = 0.03) compared with UC. translate into a statistically significant OS benefit. In 2012, Lin et al. [30] examined the effects of NAC in Taken together, these results show that classic NAC the treatment of MIBC in patients with npUC vs those regimens have only a modest role in MIBC with VH, with pUC. In their study, the rate of downstaging to often not providing a survival benefit. Fortunately, pT0 was higher in NAC-treated patients with both 8 M. ALVAREZ-MAESTRO ET AL. Table 2. Summary of NAC regimens, locoregional therapy, length of follow-up, oncological outcomes and toxicity of the studies considered for review. Loco- Follow- regional up, Authors NAC regimens therapy months Oncological outcomes Notes Bandini *Carboplatin: 20 (8.3%) RC 26 1-year RFS = 76,9% *% relative to patients undergoing NAC in the et al. Cisplatin 203 (83.9%) study. [27] Unknown: 19 (7.9%) At univariate Cox regression, npUC did not Median NAC cycles = 3 predict recurrence after RC. Bandini **Carboplatin = 1.6% RC 29 §CSS **% of patients undergoing NAC + RC is not et al. CMV/MVEC = 0.7% UC = 116 months available; ***when considering npUC, % include [29] GC = 6.9% SCC = 33 months both pure and combined VH; §median CSS of MVAC = 3.4% MPUC = 28 months patients receiving NAC + RC no NAC = 77.2% ADC = 107 months Other = 3.3% SC = 46 months Unknown = 7% Sarcoma = 12 months*** RT to the primary = 5% Brimo GC = 68% RC 3–120 disease progression in 45% At multivariate analysis VH resulted a predictor of et al MVAC = 32% at mean FU of 19.6 months recurrence but not of survival [28] cancer related deaths in 30% at a mean FU of 21.6 months Dotson NA RC 31.9 2-year OS (RC vs NAC + et al RC) = 54.8% vs 45.7% [19] Kamat NA RC 1–182 Pathological downstaging et al 63% [23] Pathological upstaging 21% 5-year OS = 63% Lin et al *MVAC = 42% RC 18 Downstaging = 16.7% *N° referring to patients with npUC undergoing NC [30] GC = 25% In the group of npUC, NAC Gemcitabine did not confer a significant +carboplatin = 33% survival benefit. Lynch ifosfamide+doxorubicine 47 RC NA Median OS = 159.5 months et al +etoposide 1 M+ 5-year CSS = 79% [26] +cisplatin = 54% Downstaging = 62% etoposide +cisplatin = 15% MVAC = 10% paclitaxel+methotrexate +cisplatin = 6% cisplatin+gemcitabine +ifosfamide = 4% etoposide+doxorubicin +cisplatin = 4% ifosfamide +doxorubicine = 2% gemcitabine +cyclophosphamide = 2% gemcitabine+doxorubicin +paclitaxel = 2% Matulay NA RC NA Median OS et al SCC – RC [20] alone = 25.4 months SCC – NAC + RC = 34.0 months (P = 0.34) Meeks GC = 21 RC = 93% 28 NAC+RC vs RC alone et al GC+sunitinib = 2 PC = 7% 2-year recurrence [24] gemcitabine rate = 33% vs 62% +carboplatin = 2 (P > 0.05) paclitaxel+GC = 3 2-year CSM = 66% vs 57% MVAC = 1 (P > 0.05) 2-year OM = 71% vs 84% (P > 0.05) Downstaging to pT0 = 45% vs 13% pT0 had better OS, CSS and RFS. Minato UC RC UC Recurrence (SCC vs et al MVAC = 62.1% 48 UC) = 88.9% vs 48.3% [22] GC = 37.9% Deaths (SCC vs UC) = 77.8% SCC SCC vs 48.3% MVAC = 22.2% 16 GC = 77.8% (Continued) ARAB JOURNAL OF UROLOGY 9 preliminary findings on the activity of neoadjuvant Cisplatin-based NAC followed by RC and pelvic lymph pembrolizumab in patients with MIBC and predomi- node dissection is the standard of care for cisplatin-eligible nant VH move to the direction of broadening the patients. There is no currently approved NAC for cisplatin- inclusion criteria of neoadjuvant immunotherapy trials ineligible patients, so these patients should directly undergo also to this kind of patient. Indeed, in a very recent RC. There is no role of carboplatin and gemcitabine combina- article, Necchi et al. [33] showed that even if an overall tion. Dose-dense (dd) or accelerated MVAC was evaluated as substantially lower activity of pembrolizumab was NAC following a modest size randomised phase III trial found in patients with predominant VH, in patients demonstrating improved long-term survival compared to with predominant VH, a substantially lower activity of conventional MVAC in UC. Three or four cycles of dd-MVAC pembrolizumab was found, as the pT0 rate was 16% were tested in combination with granulocyte growth factor (95% CI 3.4–40) and the pT ≤1 rate was 42% (95% CI support in the neoadjuvant setting in two smaller non- 21–67). However, there was significant heterogeneity randomised phase II trials with results similar to those in this group: in fact, six of seven patients with SCC observed in SWOG 8710 [34,35]. In a real-world experience achieved a pT ≤1 response, and two of three patients study of dd-MVAC followed by RC, 345 patients were with a LEL variant achieved a pT0 response (the included with 85% having high-risk features (HRFs) including remaining patient refused RC but obtained a clinical cT3–T4 disease, hydronephrosis, and VH. In all, 30% of the T0 response on re-TURBT). patients had pCR (pT0N0) and 49.3% patients with ≤pT1N0. The role of NAC in VH bladder cancers has yet to be validated in RCTs. Several case series have reported experiences with NAC in the setting of VH. The impact Discussion of cisplatin-based NAC before RC for high-grade MIBC The standard of care for MIBC is NAC followed by RC has been well established, with RCTs showing and pelvic lymph node dissection. A pCR occurs in improved survival outcomes. Regimens of MVAC or a wide range of cases (20–35%), and tumour down- CG have been shown to increase OS with an absolute staging to NMIBC is obtained in ~50% of cases. benefit of 5%. Despite these studies showing a clear Unfortunately, several limitations affected the use of survival benefit, no RCTs have focussed on the rarer NAC in clinical practice, and patients who have residual and more aggressive VH subtypes of UC of the bladder. MIBC after RC have a high likelihood of relapse and These may include UCs with any component of VH death from metastatic bladder cancer. subtype, or purely VH subtypes with no UC Table 2. (Continued). Loco- Follow- regional up, Authors NAC regimens therapy months Oncological outcomes Notes Necchi Pembrolizumab RC 13.2 *pT0 rate = 37% vs 16% vs (Overall – predominant VH – non-predominant et al 53% vs 39% VH – pUC) [33] pT ≤1 rate = 55% vs 42% vs 67% vs 56% In SCC, pT ≤1 rate = 86% In LEL pT0 rate = 67%. Pokuri Ciplatin based = 96% RC NA Histological type only et al non-cisplatin based = 4% predictor of pT0 response to [14] NAC OR 0.09, 95% CI 0.021– 0.380), P = 0.001 Scosyrev MVAC RC NA 5-year OS (pUC vs npUC) et al cT2 RC only = 61% vs 54% [13] cT2 NAC + RC = 64% vs 73% cT3-4a RC only = 42% vs 34% cT3-4a NAC + RC = 46% vs 58% Siefker- 3X Ifosfamide, Doxorubicin, RC 85.3 5-year CSS Radtke Gemcitabine + 4X npUC = 50% et al Cisplatin, Gemcitabine, pUC = 83% (P > 0.05) [31] Ifosfamide. For MPUC, 5-year CSS = 54% and OS = 54% Stensland NA RC 11.2 RC alone and NAC + RC did not et al differ. [21] Sui et al NA RC NA No survival difference between [25] NAC and RC alone observed in patients with ≥cT2 MPUC (Continued) 10 M. ALVAREZ-MAESTRO ET AL. Table 2. (Continued). Loco- Follow- regional up, Authors NAC regimens therapy months Oncological outcomes Notes Vetterlein NA RC 50.9 Median OS (months, NAC+RC et al vs RC only) [32] MPUC = 51.7 vs 29.0 Sarcomatoid = 27.1 vs 15.0 SCC = 26.2 vs 25.4 ADC = 37.2 vs 32.0 NE 34.7 vs 17.3* Other = NA vs 71.9 *statistically significant OS benefit for NAC only in patients with NE tumours. ADC: adenocarcinoma; NE: neuroendocrine; SC: small-cell. component. Prognosis is diverse for VH and there is studies [32]. Indeed, a survival benefit of adjuvant a lack of evidence on the ideal treatment approach. chemotherapy has also not been identified for patients Around 25% of MIBC cases have associated variant who had UC with concomitant variant or pure VH [39]. morphologies. While patients with a minor VH com- The effect of chemotherapy on VH bladder cancer ponent are treated like conventional UC, there are has also been assessed with trimodal bladder-sparing no definitive data to guide the therapy of those therapy comprising radiation, chemotherapy, and with a major or pure variant component. Multiple maximal TURBT. One study grouped all VHs together studies have suggested that some HVs are asso- and found that the complete response rate after induc- ciated with adverse pathological features and out- tion chemoradiation was 82% compared to 83% in comes, particularly micropapillary, plasmacytoid, pure UC [40]. There was a non-significant difference and small-cell histology [2,36]. However, other data in the 5- and 10-year OS rates (52% and 42% for VH vs suggest that only the pure variants predominantly 61% and 42% for pUC). The unique nature of VH blad- micropapillary or small cell and not mixed variant der cancers suggests a need to identify treatment histologies mostly with squamous, adenocarcinoma, plans tailored to specific VHs. Several studies have sarcomatoid, and lymphoepithelioma components evaluated the role of NAC in this setting with varying were associated with poor outcomes compared to results for each VH, indicating that other novel meth- pUC patients [37]. According to our present sys- ods, such as genome sequencing, may provide further tematic review, there is evidence supporting NAC direction on the appropriate use of NAC. Studies have with cisplatin and etoposide for neuroendocrine/ shown that p53-like bladder cancers are consistently small-cell tumours [26], although controlled data resistant to NAC while cancers with mutations in fibro - similar to small-cell lung cancer does not exist. In blast growth factor receptor 3 (FGFR3) may respond to UC with squamous and glandular differentiation, the targeted therapies, suggesting that the use of NAC data on NAC are controversial: some studies have may be aided by gene expression profiling [41]. demonstrated an advantage with the downstaging Data suggest that precision medicine by selecting of disease while others have shown a poor patients likely to benefit with cisplatin-based NAC response. Interestingly, patients with predominant may be possible with further validation. Today, dis- SCC VH achieved 86% pT ≤1 response rate and tinct genomic alterations in DNA damage response 67% of LEL variant patients achieved a pT0 pathways and transcriptomic molecular subtypes in response with neoadjuvant pembrolizumab, sug- MIBC have been linked with varied response to NAC, gesting that these variants may be more sensitive suggesting that precision medicine may be possible. to immunotherapy [33]. In micropapillary UC Patients harbouring tumours without the sensitive (MPUC), due to paucity of data, the recommenda- molecular alterations (genomic or transcriptomic) tions include immediate RC or NAC followed by RC may also exhibit pCR, suggesting that these assays [22–24]. In plasmacytoid UC, the role of NAC is cannot currently be used to deny cisplatin-based NAC unclear due to small retrospective studies with dif- to cisplatin-eligible patients off-trial [42]. However, fering chemotherapy regimens. while these platforms require optimal prospective Although some studies have shown it to be chemo- validation to enable their routine use in the clinic, sensitive, others have suggested that even after there are still several existing challenges due to achieving pCR following NAC, survival, and prognosis tumour heterogeneity, clonal evolution with treat- remains poor [38]. Similarly, in sarcomatoid UC, the ment, assay result turnaround time and costs, making lack of benefit of NAC has been shown in multiple many of these tests impractical to use in current ARAB JOURNAL OF UROLOGY 11 routine clinical practice. Nevertheless, non- [6] Winquist E, Kirchner TS, Segal R, et al. Neoadjuvant chemotherapy for transitional cell carcinoma of the randomised trials are ongoing to select patients bladder: a systematic review and meta-analysis. with sensitising genomic alterations and MIBC who J Urol. 2004;171:561–569. attain clinical CR with cisplatin-based NAC for [7] Vale C. Neoadjuvant chemotherapy in invasive bladder a bladder-sparing approach (NAC02710734, cancer: a systematic review and meta-analysis. Lancet. NAC03609216). Moreover, given the promising pCR 2003;361:1927–1934. [8] Vale CL. 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The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: A systematic review

The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: A systematic review

Abstract

Objective To systematically review the evidence about the effect of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) with pure urothelial carcinoma (pUC) in radical cystectomy (RC) candidates affected by variant histology (VH) bladder cancer. Methods A review of the current literature was conducted through the Medline and National Center for Biotechnology Information (NCBI) PubMed, Scopus databases in May 2020. The updated Preferred Reporting Items for Systematic...
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© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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2090-598X
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10.1080/2090598X.2021.1994230
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Abstract

ARAB JOURNAL OF UROLOGY 2022, VOL. 20, NO. 1, 1–13 https://doi.org/10.1080/2090598X.2021.1994230 REVIEW ONCOLOGY/RECONSTRUCTION The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: A systematic review a b b a a Mario Alvarez-Maestro , Francesco Chierigo , Guglielmo Mantica , J. M. Quesada-Olarte , D. M. Carrion , a a a a Juan Gomez-Rivas , Alvaro Pinto-Marin , Alfredo Aguilera Bazan and Luis Martinez-Piñeiro a b Department of Urology, Hospital Universitario La Paz, Madrid, Spain; Department of Urology, Policlinico San Martino Hospital, University of Genova, Genoa, Italy ABSTRACT ARTICLE HISTORY Received 23 January 2021 Objective: To systematically review the evidence about the effect of neoadjuvant chemother- Accepted 20 April 2021 apy (NAC) for muscle-invasive bladder cancer (MIBC) with pure urothelial carcinoma (pUC) in radical cystectomy (RC) candidates affected by variant histology (VH) bladder cancer. KEYWORDS Methods: A review of the current literature was conducted through the Medline and National Bladder cancer; neoadjuvant Center for Biotechnology Information (NCBI) PubMed, Scopus databases in May 2020. The chemotherapy; systematic updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were review; radical cystectomy; followed for this systematic review. Keywords used were ‘bladder cancer’, ‘bladder carcinoma’, variant histology urothelial cancer ‘bladder tumour’ and ‘bladder cancer variants’ and ‘neoadjuvant chemotherapy’. Only original articles in English published after 2000 and reporting oncological outcomes a series of more than five patients with VH were included. We excluded series in which the oncological out- comes of patients with pUC and VH were undistinguishable. Results: The literature search identified 2231 articles. A total of 51 full-text articles were assessed for eligibility, with 17 eventually considered for systematic review, for a cohort of 450,367 patients, of which 5010 underwent NAC + RC. The median age at initial diagnosis ranged from 61 to 71 years. Most patients received cisplatin-gemcitabine, methotrexate- vinblastine-adriamycin-cisplatin, or carboplatin-based chemotherapy. Only one study reported results of neoadjuvant immunotherapy. The median follow-up ranged from 1 to 120 months. The results showed that squamous cell carcinoma (SCC) is less sensitive to NAC than pUC and that SCC predicts poorer prognosis. NAC was found to be a valid approach in treating small cell carcinoma and may have potential benefit in micropapillary carcinoma. Conclusions: NAC showed the best oncological outcomes in small cell variants and micro- papillary carcinoma, while NAC survival benefit for SCC and adenocarcinoma variants needs further studies. Drawing definite considerations on the efficacy of NAC in VH is complicated due to the heterogeneity of present literature. Present results need to be confirmed in randomised controlled trials. Introduction common variants [3,4]. A population-based study con- ducted on Surveillance, Epidemiology and End Results Bladder cancer is the most common neoplasm of the (SEER) data, reported an annual incidence rate (calcu- urinary tract and worldwide the 11th most diagnosed lated according to the total USA population) for SCC of cancer [1]. In most cases, bladder cancer is a pure 903 cases/year, 450 for adenocarcinoma and 447 for urothelial carcinoma (pUC) but, in around 10–30% of neuroendocrine tumours, while pUC was >50-times patients, bladder cancer presents with a non-pure UC more common than any VH [5]. The impact of cisplatin- (npUC) or with pure variant histology (VH) without based neoadjuvant chemotherapy (NAC) before RC for a UC component. Unlike pUC, the true prevalence, high-grade muscle-invasive bladder cancer (MIBC) has treatment options, and prognosis of these VHs are been well established, with meta-analyses of prospec- not well characterised. In an institutional study asses- tive trials showing a 5–7% absolute overall survival sing the incidence of VH in patients treated with radi- (OS) [6–11]. No randomised controlled trials (RCTs) cal cystectomy (RC), 10.2% were found with squamous have focussed on the rarer and more aggressive VH cell carcinoma (SCC), 8.3% with micropapillary carci- subtypes of UC of the bladder. Prognosis is diverse for noma, 2.2% with glandular, 2.0% with sarcomatoid VH and there is a lack of evidence on the ideal treat- variant, 1.8% with small cell, 0.9% with lymphoepithe- ment approach. Today, RC is still the ‘gold standard’ for lial, 3.2% with mixed variants, and 3.1% with other both pUC MIBC and MIBC with VH [1]. In order to variants [2]. These findings are consistent with other improve the low 5-year survival provided by RC; cispla- two institutional studies, in which SCC, sarcomatoid, tin-based NAC has been used over the last three glandular and small cell were found to be the most CONTACT Mario Alvarez-Maestro malvarezmaestro@hotmail.com Department of Urology, Hospital Universitario La Paz, Madrid, Spain © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 M. ALVAREZ-MAESTRO ET AL. decades. Nevertheless, the literature is scant regarding of both pUC and npUC patients in which the oncolo- the impact of different rare variants on the response to gical outcomes of patients with pUC and of those with NAC, while npUC histology has been found to have npUC could not be distinguished. a different response to palliative systemic therapies [9]. Some of the few available studies regarding NAC Data extraction design found a survival benefit in patients with neuroendo- crine tumours and in those with squamous and gland- The overall risk of bias and Levels of Evidence (LoE) ular differentiation [12]. On the contrary, the presence were assessed by the three reviewers using the Risk Of of bladder cancer VHs was associated with lower rates Bias In Non-randomised Studies – of Interventions of response to NAC in other studies [13,14]. (ROBINS-I) tool recommended by Cochrane and the Considering this, the aim of the present systematic Oxford Centre for Evidence-Based Medicine (OCEBM) review was to provide the most recent and updated criteria [17,18]. Variables that were recorded, when evidence about the effect of NAC in RC candidates with possible, included: variables related to the publication VH bladder cancer. (year, country, design of the study); demographics (sample size, age, gender), histology at transurethral resection of bladder tumour (TURBT) or RC, TNM stage, Methods NAC regimens given, type of loco-regional therapy, follow-up, oncological outcomes, and toxicity data Literature search strategy with the complications/toxicity classification used. A review of the current literature was conducted through the Medline and National Center for Statistical analysis Biotechnology Information (NCBI) PubMed, Scopus databases in May 2020. The updated Preferred Data were entered into a Microsoft Excel (version 14.0) Reporting Items for Systematic Reviews and Meta- database and then transferred to Sofastat TM 1.4.6 for Analyses (PRISMA) guidelines were followed for this Windows. Descriptive statistics were calculated for all systematic review [15]. demographic, treatment, clinical and follow-up vari- Keywords used were: ‘bladder cancer’, ‘bladder ables, and reported as median (interquartile range carcinoma’, ‘bladder tumour’ and ‘bladder cancer [IQR]) or as a proportion with percentage. variants’. We used the previous keywords as our primary search string, which combine established Results Medical Subject Headings (MeSH) terms for ‘neoad- juvant chemotherapy’ with the highly sensitive The PRISMA flow chart of the systematic review is Cochrane search strategy. The reference lists of the presented in Figure 1. We identified 2231 articles retrieved reviews were also checked and cross- from the Scopus and PubMed database searches. referenced [16]. EndNote removed 999 duplications, 947 articles were The searches were performed independently by discarded according to title, non-English language, two researchers (F.C. and G.M.), and any disagreement and type of article (case reports, letters, editorials, resolved by a third independent researcher (M.A.M.). reviews, etc.), and further 234 after reading the The initial screening was done on the base of titles and abstract. Overall, 51 full-text articles were assessed for abstracts. eligibility: eight articles were excluded because they considered less than five patients with VH undergoing NAC, 15 because the articles did not report oncological Inclusion and exclusion criteria results, and 11 because oncological results were not All papers published after the year 2000, concerning divided by histological type. studies conducted on humans for NAC for bladder A summary of the variables is shown in Table 1. cancer were considered for the review. Duplications Of the 17 articles included in the present review, 13 were excluded using the dedicated tool on EndNote were retrospective studies and three were clinical software. Only original articles (randomised controlled trials (Table 1) [13,14,19–33]. The median age at trials, cohort studies, case-control studies) for series of initial diagnosis ranged from 61 to 71 years and more than five patients were included. Other publica- males greatly outnumbered females. The cohort of tions such as reviews, commentaries, editorials, and patients we considered comprised 450,367 patients, letters to the editor were excluded. The most recent of which 5010 underwent NAC and RC. Due to the publication was considered if several studies evaluated vast heterogeneity in the studies, it was quite diffi - the same patient cohort. Only studies published in cult to understand how many patients with npUC English were considered. Further, only studies report- underwent NAC + RC. The clinical stage of most of ing oncological outcomes of patients with rare HVs the population studied was cT2N0. Most patients were included in the review. We also excluded series received cisplatin-gemcitabine (CG), methotrexate- ARAB JOURNAL OF UROLOGY 3 Records identified through database searching (n = 2231 ) Records after duplicates removed (n = 1232) Records excluded based on title, non‐ Records screened English language and type of article (n =1232) (n = 947), and based on abstracts (n=234) Full‐text articles excluded, with reasons (n = 31): Full‐text articles assessed ‐Less than 5 NCT pts with variant histology for eligibility (n=8) (n = 51) ‐Non‐oncological results (n=15) ‐Oncological results not divided by histology (n=11) Studies included in qualitative synthesis (n = 17 ) Figure 1. Flow diagram. vinblastine-adriamycin-cisplatin (MVAC) or carbopla- The results are consistent with those by Matulay tin-based chemotherapy, with only one reporting et al. [20], who, still using the NCBD, showed that the results of neoadjuvant immunotherapy. median OS for patients with SCC who received RC Unfortunately, five of 17 articles did not report the alone was 25.4 months compared to 34.0 months NAC regimens undergone and only one reported with NAC, although not statistically significant. NAC-related toxicities. The median follow-up ranged The NCDB was queried once again by Stensland from 1 to 120 months, averaging at ~40 months. et al. [21] for cases of localised, muscle-invasive pure Oncological results were also reported in quite dif- squamous cell bladder cancer, classified as clinical ferent ways, mainly: downstaging after NAC, recur- stage T2/3N0M0. In this study, the unweighted median rence-free survival (RFS), cancer-specific survival survival was 46 months for RC alone, and 21 months (CSS), OS, recurrence rate, and mortality rate (MR) for NAC + RC. However, in the weighted multivariate (Table 2) [13,14,19–33]. Cox model, compared to RC alone, NAC did not sig- nificantly differ with regard to OS. One major limitation of these three studies is that Squamous cell carcinoma (SCC) the NCDB lacks specific data on chemotherapy: the type, duration, and dose of chemotherapy cannot be Three studies focussed on SCC. Using data from the analysed, so NAC is probably a heterogeneous group National Cancer Database (NCDB), Dotson et al. [19] comprising multiple types of chemotherapeutic evaluated the management and survival of patients regimens. with invasive SCC treated with or without NAC. A study from Japan also tried to investigate the Although more patients were down-staged to non- efficacy of cisplatin-based chemotherapy (MVAC or invasive disease (pT < 2) in the NAC group, the 2-year CG) and prognosis of patients with UC with or without OS was not statistically significantly different, being squamous differentiation of the bladder. In this study, 54.8% for RC alone and 45.7% for NAC + RC. none of the patients with SCC achieved pathological Included Eligibility Screening Identification 4 M. ALVAREZ-MAESTRO ET AL. Table 1. Summary of study design and pre-therapy patients’ characteristics of the studies considered for review. Study Sample Authors design size Age, years Gender Histology TNM Stage Notes Bandini R 950 68 NA §206 pUC cT stage §Histology at TURBT et al. (242 36 npUC cT2 = 59.9% [27] NAC) cT3–4 = 37.6% Unknown = 2.5% pT stage pT0 = 32.6% pTa/pTis = 8.3% pT1 = 6.6% pT2 = 17.4% pT3 = 26.9% pT4 = 8.3% pN Stage pNx = 1.2% pN0 = 81.4% pN1 = 8.3% pN2 = 8.7% pN3 = 0.4% Bandini R 285 68 2331 Male **UC = 78% **cT stage *Histology at RC; **% of pts et al. (450 527 SCC = 9,9% <cT2 = 17.7% undergoing NAC + RC is not [29] NAC) Female MPUC = 3% cT2 = 57.1% available; ***when considering ADC = 2,3% cT3-4 = 12.5% npUC, % include both pure and Small cell = 1,9% Unknown = 12.7% combined VH Sarcoma = 1,6% cN stage Other = 3,3%*** cN0 = 43.6% cN1 = 5.4% cN2 = 3.6% cN3 = 0.4% cNx = 16.2% Unknown = 30.9% pTN stage <pT2N0M0 = 14% pT0N0M0: 3.8% pT2N0M0 = 12.4% pT3-T4N0M0 = 27.5% pTanyN +M0 = 37.3% pTanyNx = 4.9% Brimo R 165 65 119 Male UC = 76% pT stage et al. 46 npUC = 24% pT0 = 16% [28] Female pTis = 14% pTa = 2% pT1 = 9% pT2 = 17% pT3 = 26% pT4 = 16%; pN stage N0 = 68% N1 = 13% N2 = 15% N3 = 4% Dotson R 671 61 NA SCC cT stage et al. (48 cT2 = 75% [19] NAC) cT3 = 25% pT stage: <pT2 = 10.4% pT2 = 16.7% pT3 = 50% pT4 = 16.7% Unknown = 6.3% pN+ = 18.7% Kamat R 100 66 21 Male MPUC cT stage et al. (23 3 Tis = 4.4% [23] NAC) Female Ta = 0% T1 = 39.1% T2 = 30.4% T3 = 13.0% T4a = 13% pT stage pT0 = 39.1% pTis = 17.4% pT1 = 4.4% pT2 = 4.4% pT3 = 17.4% pT4 = 4.4% N+ = 13% (Continued) ARAB JOURNAL OF UROLOGY 5 Table 1. (Continued). Study Sample Authors design size Age, years Gender Histology TNM Stage Notes Lin et al. R 195 66 *7 Male pUC = 161 *cT stage *N° referring to pts with npUC [30] (37 5 npUC = 34 cT2 = 58% undergoing NC NAC) Female cT3 = 25% cT4 = 17% Lynch R 172 67 41 Male SC only = 22 cT stage et al. (48 7 >50% SC = 18 ≤ cT1N0 = 1 [26] NAC) Female <50% SC = 8 cT2N0 = 30 cT3-4aN0 = 17 Matulay R 260 NA *UC = 3896 cT2-4N0M0 * N° referring to NAC + RC patients et al. (75 SCC = 75 [20] NAC) Meeks R 44 71 26 Male MPUC NA et al. (29 18 [24] NAC) Female Minato R 38 66 29 Male UC = 29 UC et al. 9 SCC = 9 T3 = 93.6% [22] Female T4 = 3.4% SCC T3 = 88.9% T4 = 11.1% Necchi P-II 114 66 99 Male pUC = 80 cT stage et al. CT (111 15 npUC = 34 T2 = 54% [33] NAC) Female 33% SCC T3 = 44% 17% nested T4 = 3.6% 12% MPUC 9% LEL, 6% sarcomatoid 6% ADC+SCC 3% ADC 3% small cell 3% plasmacytoid 3% spindle cell 3% clear cell 3% SCC+SC Pokuri R 50 67,5 41 Male pUC = 52% Clinical stage et al. 9 npUC = 48% cT2N0 = 62% [14] Female cT3N0 = 22% cT4N0 = 16% Scosyrev CT 307 VH VH – NAC pUC = 236 VH *patient % relative to those who et al. (124 NAC + + RC SCC = 37 cT3–cT4a = 59% received NAC + RT [13] NAC) RC = 60 69% ADC = 20 Male SCC+ADC = 2 31% Other = 2 Female VH VH – RC RC = 65 85% Male 15% Female pUC pUC – pUC NAC + NAC + cT3–cT4a = 59%* RC = 63 RC 86% Male 14% Female pUC pUC + RC RC = 62 79% Male 21% Female Siefker- P-II 65 62,5 50 Male pUC = 57% cT stage of bladder/ *VH ≤50% of the specimen Radtke CT 15 VH = 43% urethra tumor et al. Female (MPUC 46% of VH)* (n = 60) [31] cT2 = 37 cT3b = 18 cT4a = 5 Tumor in the renal pelvis or ureter = 5 Stensland R 828 63,5 29 Male SCC cT stage et al. (53 16 T2 = 79.2% [21] NAC) Female T3 = 20.8% (Continued) 6 M. ALVAREZ-MAESTRO ET AL. Table 1. (Continued). Study Sample Authors design size Age, years Gender Histology TNM Stage Notes Sui et al. R 439188 pUC = 71,1 pUC *UC = 3052 MPUC * N° referring to pts undergoing [25] (3083 Male MPUC = 31 cT stage NAC + RC NAC) 75.4% Tx 17.4% Female T0 = 0% 24.6% Tis = 5.2% T1 = 29.8% T2 = 35.4% T3 = 7.1% T4 = 5.1% cN stage N0 = 70% N+ = 9.1% Nx = 20.9% cM stage M0 = 95.3% M1 = 4.7% MPUC = 69.9 MPUC UC Male cT stage 78.3% Tx 16.5% Female T0 0.3% 21.7% Tis 47.2% T2 11.5% T3 1.6% T4 1.8% cN stage N0 77.4% N + 1.8% Nx 20.8% cM stage M0 98.1% M1 1.9% Vetterlein R 2018 66,7 Male MPUC = 7.6% cT2N0 = 65.1% et al. (369 62.4% sarcomatoid = 15.1% ≥cT2 and/or [32] NAC) Female SCC = 40.1% cN1 = 34.9% 37.4% ADC = 17.7% NE = 13.3% other = 6.1% ADC: adenocarcinoma; NE: neuroendocrine; P-II CT: phase II clinical trial; R: retrospective; SC: small-cell. complete response (pCR) to NAC and the proportion of year OS rate of 63% in patients treated with NAC + down-staging was lower in patients with SCC than in RC, which was not significantly different from what ones with pUC [22]. The median follow-up was 16 and was observed for the patients treated with upfront 48 months in patients with SCC and pUC, respectively. RC, who had a 5-year OS rate of 71%. Interestingly, After RC, recurrence developed in 88.9% and 48.3% of patients who had non-MIBC (NMIBC), delaying sur- the patients with SCC and pUC, respectively; and 77.8% gery for neoadjuvant therapy demonstrated a trend and 48.3% died in the SCC and pUC groups, respectively. toward a decreased median survival and 5-year sur- From these results, it appears that SCC is less sensi- vival rate compared to upfront surgery. tive to NAC than pUC, and that SCC predicts poorer Another study reported that the rates of recur- prognosis. However, there is a need for larger, prospec- rence (33% vs 62%), cancer-specific mortality (66% tive investigations, with design confronting different vs 57%) and overall mortality (71% vs 84%) were NAC regiments in patients with SCC. not different at 2 years between patients who did or did not receive NAC. However, down-staging to pT0 occurred in 45% of patients receiving NAC, Micropapillary carcinoma compared with 13% of those who underwent upfront RC (P = 0.049). Despite micropapillary his- We identified three studies focussing on micropapillary tology, those with pT0 had improved outcomes carcinoma. Kamat et al. [23] retrospectively reviewed after RC, with a lower rate of recurrence, lower data of 100 patients with micropapillary carcinoma, 23 bladder cancer-specific mortality and longer time of them undergoing NAC + RC. They observed a 5‒ ARAB JOURNAL OF UROLOGY 7 to death. Therefore, the authors [24] concluded npUC (P = 0.048) and pUC (P < 0.001), as compared that patients with the micropapillary variant of UC to those in each group who did not receive NAC. should not be excluded from consideration However, NAC was not a significant predictor of OS for NAC. for patients with npUC in a Cox multivariate model Sui et al. [25] analysed data of from the NCBD, in (P = 0.54) and, among all patients treated with NAC, which 94 patients with ≥cT2 disease were identified. In mixed histology was found to be a predictor of poorer this study, there was not a statistically significant dif- survival. ference in median OS between patients who received In addition, Pokuri et al. [14] found that the odds of NAC and those who did not. a pT0 response for pUC were approximately 11-times greater relative to cancers with VH features or mixed tumours (OR 0.09, 95% CI 0.021–0.380; P = 0.001), Small cell carcinoma including squamous, glandular differentiation, small cell, micropapillary, sarcomatoid, nested component, Lynch et al. [26] identified 125 patients with small cell lymphoepithelioma-like (LEL), and plasmacytoid UC with a clinical stage ≤cT4aN0M0. Of these, 95 were variants. surgical candidates: 48 received NAC and 47 under- A secondary analysis of the Southwest Oncology went upfront RC. Neoadjuvant treatment was asso- Group (SWOG)-directed intergroup randomised trial ciated with improved OS and CSS compared with S8710 of neoadjuvant MVAC followed by RC vs RC initial RC (median OS: 159.5 vs 18.3 months, alone for treatment of locally advanced UC of the P < 0.001; 5-year CSS: 79% vs 20%, P < 0.001). NAC bladder gave evidence of a survival benefit from che- resulted in pathological downstaging to ≤pT1N0 in motherapy in patients with mixed tumours (HR 0.46, 62% of tumours compared with only 9% treated with 95% CI 0.25–0.87; P = 0.02). Moreover, there was mar- initial RC. Although limited by a small sample size with ginal evidence that the survival benefit of NAC in a retrospective analysis, and this being the only article patients with mixed tumours was greater than it was dealing solely with small cell carcinoma, these data for patients with pUC. These analyses also showed that suggest NAC as a valid approach in treating small cell the estimated improvement in 5-year survival asso- carcinoma of the bladder. ciated with MVAC was much greater in magnitude among patients with npUC than among patients with Articles studying more than one npUC histology pUC [13]. A phase II clinical trial of sequential NAC with ifos- The other nine studies we included in the present famide, doxorubicin, and gemcitabine, followed by review considered npUC without discriminating for cisplatin, gemcitabine, and ifosfamide showed that histological type or considered many histological the presence of VH was associated with an inferior variants. 5-year CSS of 50% as compared to 83% for pUC (log- In 2019, Bandini et al. [27], in a study aimed at rank P = 0.02). In this series, the presence of micropa- modelling 1-year RFS after NAC + RC in patients with pillary histology was associated with a 5-year OS and cT2–4N0M0 bladder cancer, showed that npUC was CSS of 54%. A pUC histology was also a significant not a predictor of recurrence after RC at univariable factor to disease-specific survival (relative risk 0.35 for Cox regression model analysis. On the contrary, UC vs mixed, P = 0.03). This clinical trial was the only a multicentric study which also investigated prognos- study included in our review to report NAC-related tic pathological factors in RC after NAC showed that VH toxicities. There was only one death due pneumonia was a predictor of recurrence, but not of cancer-related during neutropenia. In all, 6% of patients had Grade 4 death [28]. toxicities (myocardial infarction, platelet transfusion, In 2020, a multi-institutional study aimed to exam- and vomiting), while the most frequent Grade 3 toxi- ine the effect of NAC on bladder cancer with different cities were infection (38%), febrile neutropenia (22%), histological variants [29]. Of the 450 NAC-treated and mucositis 18%, and platelet transfusion (12%) [31]. patients, only patients with SCC had had worse CSS In 2017, Vetterlein et al. [32] assessed the effect of (median CSS, 33 vs 116 months; P < 0.001) and higher NAC on OS after RC in patients with HVs, finding an OS mortality rates (hazard ratio [HR] 2.1; P = 0.03) com- benefit for NAC only in patients with neuroendocrine pared with those with pUC. After adjusting for NAC, tumours (HR 0.49, 95% CI 0.33–0.74; P = 0.001). For only SCC showed a lower rate of clinical-to- other HVs, even if NAC decreased the frequency of non- pathological downstaging (odds ratio [OR] 0.4; organ confined disease at the time of RC, this did not P = 0.03) compared with UC. translate into a statistically significant OS benefit. In 2012, Lin et al. [30] examined the effects of NAC in Taken together, these results show that classic NAC the treatment of MIBC in patients with npUC vs those regimens have only a modest role in MIBC with VH, with pUC. In their study, the rate of downstaging to often not providing a survival benefit. Fortunately, pT0 was higher in NAC-treated patients with both 8 M. ALVAREZ-MAESTRO ET AL. Table 2. Summary of NAC regimens, locoregional therapy, length of follow-up, oncological outcomes and toxicity of the studies considered for review. Loco- Follow- regional up, Authors NAC regimens therapy months Oncological outcomes Notes Bandini *Carboplatin: 20 (8.3%) RC 26 1-year RFS = 76,9% *% relative to patients undergoing NAC in the et al. Cisplatin 203 (83.9%) study. [27] Unknown: 19 (7.9%) At univariate Cox regression, npUC did not Median NAC cycles = 3 predict recurrence after RC. Bandini **Carboplatin = 1.6% RC 29 §CSS **% of patients undergoing NAC + RC is not et al. CMV/MVEC = 0.7% UC = 116 months available; ***when considering npUC, % include [29] GC = 6.9% SCC = 33 months both pure and combined VH; §median CSS of MVAC = 3.4% MPUC = 28 months patients receiving NAC + RC no NAC = 77.2% ADC = 107 months Other = 3.3% SC = 46 months Unknown = 7% Sarcoma = 12 months*** RT to the primary = 5% Brimo GC = 68% RC 3–120 disease progression in 45% At multivariate analysis VH resulted a predictor of et al MVAC = 32% at mean FU of 19.6 months recurrence but not of survival [28] cancer related deaths in 30% at a mean FU of 21.6 months Dotson NA RC 31.9 2-year OS (RC vs NAC + et al RC) = 54.8% vs 45.7% [19] Kamat NA RC 1–182 Pathological downstaging et al 63% [23] Pathological upstaging 21% 5-year OS = 63% Lin et al *MVAC = 42% RC 18 Downstaging = 16.7% *N° referring to patients with npUC undergoing NC [30] GC = 25% In the group of npUC, NAC Gemcitabine did not confer a significant +carboplatin = 33% survival benefit. Lynch ifosfamide+doxorubicine 47 RC NA Median OS = 159.5 months et al +etoposide 1 M+ 5-year CSS = 79% [26] +cisplatin = 54% Downstaging = 62% etoposide +cisplatin = 15% MVAC = 10% paclitaxel+methotrexate +cisplatin = 6% cisplatin+gemcitabine +ifosfamide = 4% etoposide+doxorubicin +cisplatin = 4% ifosfamide +doxorubicine = 2% gemcitabine +cyclophosphamide = 2% gemcitabine+doxorubicin +paclitaxel = 2% Matulay NA RC NA Median OS et al SCC – RC [20] alone = 25.4 months SCC – NAC + RC = 34.0 months (P = 0.34) Meeks GC = 21 RC = 93% 28 NAC+RC vs RC alone et al GC+sunitinib = 2 PC = 7% 2-year recurrence [24] gemcitabine rate = 33% vs 62% +carboplatin = 2 (P > 0.05) paclitaxel+GC = 3 2-year CSM = 66% vs 57% MVAC = 1 (P > 0.05) 2-year OM = 71% vs 84% (P > 0.05) Downstaging to pT0 = 45% vs 13% pT0 had better OS, CSS and RFS. Minato UC RC UC Recurrence (SCC vs et al MVAC = 62.1% 48 UC) = 88.9% vs 48.3% [22] GC = 37.9% Deaths (SCC vs UC) = 77.8% SCC SCC vs 48.3% MVAC = 22.2% 16 GC = 77.8% (Continued) ARAB JOURNAL OF UROLOGY 9 preliminary findings on the activity of neoadjuvant Cisplatin-based NAC followed by RC and pelvic lymph pembrolizumab in patients with MIBC and predomi- node dissection is the standard of care for cisplatin-eligible nant VH move to the direction of broadening the patients. There is no currently approved NAC for cisplatin- inclusion criteria of neoadjuvant immunotherapy trials ineligible patients, so these patients should directly undergo also to this kind of patient. Indeed, in a very recent RC. There is no role of carboplatin and gemcitabine combina- article, Necchi et al. [33] showed that even if an overall tion. Dose-dense (dd) or accelerated MVAC was evaluated as substantially lower activity of pembrolizumab was NAC following a modest size randomised phase III trial found in patients with predominant VH, in patients demonstrating improved long-term survival compared to with predominant VH, a substantially lower activity of conventional MVAC in UC. Three or four cycles of dd-MVAC pembrolizumab was found, as the pT0 rate was 16% were tested in combination with granulocyte growth factor (95% CI 3.4–40) and the pT ≤1 rate was 42% (95% CI support in the neoadjuvant setting in two smaller non- 21–67). However, there was significant heterogeneity randomised phase II trials with results similar to those in this group: in fact, six of seven patients with SCC observed in SWOG 8710 [34,35]. In a real-world experience achieved a pT ≤1 response, and two of three patients study of dd-MVAC followed by RC, 345 patients were with a LEL variant achieved a pT0 response (the included with 85% having high-risk features (HRFs) including remaining patient refused RC but obtained a clinical cT3–T4 disease, hydronephrosis, and VH. In all, 30% of the T0 response on re-TURBT). patients had pCR (pT0N0) and 49.3% patients with ≤pT1N0. The role of NAC in VH bladder cancers has yet to be validated in RCTs. Several case series have reported experiences with NAC in the setting of VH. The impact Discussion of cisplatin-based NAC before RC for high-grade MIBC The standard of care for MIBC is NAC followed by RC has been well established, with RCTs showing and pelvic lymph node dissection. A pCR occurs in improved survival outcomes. Regimens of MVAC or a wide range of cases (20–35%), and tumour down- CG have been shown to increase OS with an absolute staging to NMIBC is obtained in ~50% of cases. benefit of 5%. Despite these studies showing a clear Unfortunately, several limitations affected the use of survival benefit, no RCTs have focussed on the rarer NAC in clinical practice, and patients who have residual and more aggressive VH subtypes of UC of the bladder. MIBC after RC have a high likelihood of relapse and These may include UCs with any component of VH death from metastatic bladder cancer. subtype, or purely VH subtypes with no UC Table 2. (Continued). Loco- Follow- regional up, Authors NAC regimens therapy months Oncological outcomes Notes Necchi Pembrolizumab RC 13.2 *pT0 rate = 37% vs 16% vs (Overall – predominant VH – non-predominant et al 53% vs 39% VH – pUC) [33] pT ≤1 rate = 55% vs 42% vs 67% vs 56% In SCC, pT ≤1 rate = 86% In LEL pT0 rate = 67%. Pokuri Ciplatin based = 96% RC NA Histological type only et al non-cisplatin based = 4% predictor of pT0 response to [14] NAC OR 0.09, 95% CI 0.021– 0.380), P = 0.001 Scosyrev MVAC RC NA 5-year OS (pUC vs npUC) et al cT2 RC only = 61% vs 54% [13] cT2 NAC + RC = 64% vs 73% cT3-4a RC only = 42% vs 34% cT3-4a NAC + RC = 46% vs 58% Siefker- 3X Ifosfamide, Doxorubicin, RC 85.3 5-year CSS Radtke Gemcitabine + 4X npUC = 50% et al Cisplatin, Gemcitabine, pUC = 83% (P > 0.05) [31] Ifosfamide. For MPUC, 5-year CSS = 54% and OS = 54% Stensland NA RC 11.2 RC alone and NAC + RC did not et al differ. [21] Sui et al NA RC NA No survival difference between [25] NAC and RC alone observed in patients with ≥cT2 MPUC (Continued) 10 M. ALVAREZ-MAESTRO ET AL. Table 2. (Continued). Loco- Follow- regional up, Authors NAC regimens therapy months Oncological outcomes Notes Vetterlein NA RC 50.9 Median OS (months, NAC+RC et al vs RC only) [32] MPUC = 51.7 vs 29.0 Sarcomatoid = 27.1 vs 15.0 SCC = 26.2 vs 25.4 ADC = 37.2 vs 32.0 NE 34.7 vs 17.3* Other = NA vs 71.9 *statistically significant OS benefit for NAC only in patients with NE tumours. ADC: adenocarcinoma; NE: neuroendocrine; SC: small-cell. component. Prognosis is diverse for VH and there is studies [32]. Indeed, a survival benefit of adjuvant a lack of evidence on the ideal treatment approach. chemotherapy has also not been identified for patients Around 25% of MIBC cases have associated variant who had UC with concomitant variant or pure VH [39]. morphologies. While patients with a minor VH com- The effect of chemotherapy on VH bladder cancer ponent are treated like conventional UC, there are has also been assessed with trimodal bladder-sparing no definitive data to guide the therapy of those therapy comprising radiation, chemotherapy, and with a major or pure variant component. Multiple maximal TURBT. One study grouped all VHs together studies have suggested that some HVs are asso- and found that the complete response rate after induc- ciated with adverse pathological features and out- tion chemoradiation was 82% compared to 83% in comes, particularly micropapillary, plasmacytoid, pure UC [40]. There was a non-significant difference and small-cell histology [2,36]. However, other data in the 5- and 10-year OS rates (52% and 42% for VH vs suggest that only the pure variants predominantly 61% and 42% for pUC). The unique nature of VH blad- micropapillary or small cell and not mixed variant der cancers suggests a need to identify treatment histologies mostly with squamous, adenocarcinoma, plans tailored to specific VHs. Several studies have sarcomatoid, and lymphoepithelioma components evaluated the role of NAC in this setting with varying were associated with poor outcomes compared to results for each VH, indicating that other novel meth- pUC patients [37]. According to our present sys- ods, such as genome sequencing, may provide further tematic review, there is evidence supporting NAC direction on the appropriate use of NAC. Studies have with cisplatin and etoposide for neuroendocrine/ shown that p53-like bladder cancers are consistently small-cell tumours [26], although controlled data resistant to NAC while cancers with mutations in fibro - similar to small-cell lung cancer does not exist. In blast growth factor receptor 3 (FGFR3) may respond to UC with squamous and glandular differentiation, the targeted therapies, suggesting that the use of NAC data on NAC are controversial: some studies have may be aided by gene expression profiling [41]. demonstrated an advantage with the downstaging Data suggest that precision medicine by selecting of disease while others have shown a poor patients likely to benefit with cisplatin-based NAC response. Interestingly, patients with predominant may be possible with further validation. Today, dis- SCC VH achieved 86% pT ≤1 response rate and tinct genomic alterations in DNA damage response 67% of LEL variant patients achieved a pT0 pathways and transcriptomic molecular subtypes in response with neoadjuvant pembrolizumab, sug- MIBC have been linked with varied response to NAC, gesting that these variants may be more sensitive suggesting that precision medicine may be possible. to immunotherapy [33]. In micropapillary UC Patients harbouring tumours without the sensitive (MPUC), due to paucity of data, the recommenda- molecular alterations (genomic or transcriptomic) tions include immediate RC or NAC followed by RC may also exhibit pCR, suggesting that these assays [22–24]. In plasmacytoid UC, the role of NAC is cannot currently be used to deny cisplatin-based NAC unclear due to small retrospective studies with dif- to cisplatin-eligible patients off-trial [42]. However, fering chemotherapy regimens. while these platforms require optimal prospective Although some studies have shown it to be chemo- validation to enable their routine use in the clinic, sensitive, others have suggested that even after there are still several existing challenges due to achieving pCR following NAC, survival, and prognosis tumour heterogeneity, clonal evolution with treat- remains poor [38]. Similarly, in sarcomatoid UC, the ment, assay result turnaround time and costs, making lack of benefit of NAC has been shown in multiple many of these tests impractical to use in current ARAB JOURNAL OF UROLOGY 11 routine clinical practice. Nevertheless, non- [6] Winquist E, Kirchner TS, Segal R, et al. Neoadjuvant chemotherapy for transitional cell carcinoma of the randomised trials are ongoing to select patients bladder: a systematic review and meta-analysis. with sensitising genomic alterations and MIBC who J Urol. 2004;171:561–569. attain clinical CR with cisplatin-based NAC for [7] Vale C. Neoadjuvant chemotherapy in invasive bladder a bladder-sparing approach (NAC02710734, cancer: a systematic review and meta-analysis. Lancet. NAC03609216). Moreover, given the promising pCR 2003;361:1927–1934. [8] Vale CL. 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Journal

Arab Journal of UrologyTaylor & Francis

Published: Jan 2, 2022

Keywords: Bladder cancer; neoadjuvant chemotherapy; systematic review; radical cystectomy; variant histology urothelial cancer

References