Administration de chimiothérapie néoadjuvante pour tumeur de vessie infiltrant le muscle en vie réelle : les urologues encore trop frileux ?

16 mai 2021

Auteurs : M. Such, A. Lavolle, M.-B. Popelin, C. Thibault, E. Fontaine, C. Dariane, S. Oudard, A. Mejean, M.-O. Timsit, F. Audenet
Référence : Prog Urol, 2021, 6, 31, 332-339




 




Introduction


In France, bladder tumors had an incidence of more than 13,000 new cases in 2018 and are responsible for 5300 deaths per year (Santé publique France 2019). At the time of diagnosis, 25 to 30% of bladder tumors have infiltrated the muscle [1], and up to 30% of tumors that do not infiltrate the muscle later become secondarily infiltrating tumors [2]. The standard treatment for localized muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) based on cisplatin, in the absence of contraindication prior to radical cystectomy with extensive pelvic lymph nodes dissection [3]. Since the randomized trial published by Grossman et al. in 2003 [4], several meta-analyses have confirmed the benefit of NAC, regardless of the initial stage of MIBC, with an improvement in five-year survival of 8% [5]. Therefore, NAC is recommended for patients with good renal function (glomerular filtration rate usually greater than 60mL/min) and in good general condition [3].


Despite a large amount of evidence, the use of NAC remains limited, with approximately 20% of patients receiving treatment before cystectomy in the United States [6]. Among the concerns raised, toxicity of chemotherapy, delay in performing the surgery and possibility of more important operative complications have been put forward. However, only poor data from France on the use of NAC in real life are available. The aim of this single-center study was to present the proportion and characteristics of patients receiving NAC prior to cystectomy for localized MIBC.


Methods


Population


This study was a single-center, retrospective study including all patients who underwent cystectomy for urothelial bladder carcinoma≥pT2NxM0 between January 2013 and December 2018. The diagnosis of MIBC was based on the pathological analysis of the trans-urethral resection of bladder tumor (TURBT). Patients with infiltrating bladder tumors whose analysis showed another histology than urothelial carcinoma were excluded. Patients who received another type of neoadjuvant therapy (immunotherapy in a clinical trial) were also excluded. Extension evaluation included pelvic-abdominal and chest CT-scan, without and with injection of contrast product when the patient's renal function allowed it, or a chest CT-scan without injection and an abdominal and pelvic MRI otherwise. Every CT-scans were read by an onco-urologist-radiologist. Therapeutic strategy was discussed collegially in a multidisciplinary meeting in accordance with national committee CC-AFU guidelines.


Treatment


NAC consisted in four to six cures of high-dose MVAC (methotrexate 30mg/m2 on day one, vinblastin 3mg/m2 on day one, doxorubicin 30mg/m2 on day one and cisplatin 70mg/m2 on day one with hyperhydration before and after administration, every two weeks) or three to four cures of GC (gemcitabin 1000mg/m2 on day one, day eight and cisplatin 70mg/m2 on day one with hyperhydration before and after administration, every three weeks). Safety was assessed before each injection by a medical oncologist. A reassessment chest and abdomino-pelvic CT-scan was performed at the end of NAC.


Surgical treatment consisted in radical cystectomy (for men: removal of the bladder, prostate, seminal vesicles; for women: removal of the bladder, entire urethra, adjacent vagina and uterus) with ilio-obturator, external iliac, internal iliac and primary iliac dissection up to the crossing of the ureters. Type of urinary diversion was decided by the surgeon in agreement with the patient (transileal cutaneous ureterostomy [Bricker], neobladder or uretero-cutaneostomies). Ureteral and urethral resections were sent for extemporaneous intraoperative analysis. Histological analysis was performed by an uropathologist. Surgical complications occurring during the hospital stay were classified according to the Clavien-Dindo classification [7]. The clinical and radiological monitoring of patients was classically organized at months three, six and twelve, then every six months for at least five years.


Statistical analysis


Demographic (sex, age, ECOG/WHO-PS, glomerular filtration rate [GFR], and cN stage), surgical (urinary diversion, surgery time, blood losses, and intra- and post-operative complications) and oncological (progression and death) outcomes were analyzed. Qualitative variables were compared using the &khgr;2 test and Fisher's exact test. Quantitative variables were compared by the Wilcoxon test and the Kruskal-Wallis test. Survival curves were generated according to the Kaplan-Meier method and compared by the log-rank test. Predictors of NAC administration were sought in a multivariate analysis using a logistic regression model. A P <0.05 was considered statistically significant. Every analysis was carried out with R software version 3.6.1 (cran.r-project.org/).


Results


Population characteristics


Between 2013 and 2018, 1290 patients were treated for urothelial tumors in our center, with an average of 215 patients per year. Over the same period, an average of 35 cystectomies per year were performed. A total of 127 patients were included in this study: 30 patients (23.6%) received NAC before surgery, and 97 patients (76.4%) were treated with surgery only. Characteristics of the population were summarized in Table 1. Median age at diagnosis was 73.0 years (66.0–79.5), and 85.8% of the patients were men. Patients treated with NAC were significantly younger (66.5 versus 75.0 years, P <0.001), with a better ECOG-PS score (90.0% versus 62.9% of ECOG 0 patients, P =0.016) and better renal function (GFR 78.5 versus 56.0mL/min, P <0.001). Twenty patients (15.7%) presented pelvic lymph nodes≥1cm on the extension evaluation (cN+), with a bigger proportion in the group treated with NAC (43.0% versus 7.2%, P <0.001).


NAC methods


Among the 30 patients who received NAC, 22 (73.3%) were able to undergo full treatment, and eight patients (26.7%) could not have received all the chemotherapy due to occurrence of toxicities: one grade 4 complication (rectal bleeding complicated by septic and hemorrhagic shock), three grade 3 complications (severe infection, dental abscess, and hearing loss, respectively) and three grade 2 complications (two acute renal failure and neuropathy). For one patient, the cause of the premature cessation of chemotherapy was not known, because it was carried out in another center. The reasons for not performing neoadjuvant chemotherapy are listed in Table 2. Decreased renal function (GFR<60mL/min) was the main reason for refusing NAC (46.4% of patients). For almost a quarter of the patients (23.7%), no objective cause of refusal of NAC was found. Among the 30 patients treated with NAC, 25 (83.3%) received an MVAC protocol, four (13.3%) received a cisplatin+gemcitabine combination and one (3.3%) received a carboplatin+gemcitabine combination. Distribution of patients according to their treatment modality was shown in Figure 1. Between 2013 and 2018, the proportion of patients receiving NAC with cystectomy varied from 13.0% to 33.0% (Figure 2), but any increasing trend was identified. In multivariate analysis, cN+lymph node status and higher GFR were significantly associated with the occurrence of NAC (Table 3).


Figure 1
Figure 1. 

Repartition of the patients according to treatment modalities.




Figure 2
Figure 2. 

Proportion of patients undergoing NAC: evolution between 2013 and 2018.




Surgical management


Delay between diagnosis and cystectomy was 58.0 days [41.0–83.0] in the surgery group and 126.0 days [110.0–154.0] in the NAC group, with a median time of 37.4 days [32.0–46.0] between the end of chemotherapy and surgery. Time between diagnosis and the start of active treatment was comparable in the two groups (58.0 versus 43.0 days, P =0.135). No significant difference was found concerning the operating duration (330 versus 300min, P =0.325), rate of surgical complications (48.5% versus 50.0%, P =0.884) or length of hospitalization (16.0 days in each group, P =0.087). Intraoperative blood losses were lesser (600 versus 500mL, P =0.019) in the surgery only group. One month after cystectomy, the patients treated with NAC had a greater decrease in their GFR (−17 versus +5mL/min, P <0.01), despite a comparable rate of perioperative complications between the two groups (48.5% versus 50.0%, P =0.884). There was no significant difference in the occurrence of urinary anastomosis stenosis which needed to replace a unilateral or bilateral ureteral catheter, or a neobladder catheter (12.4% versus 10.0%, P =1.0).


Oncological results


Radiological reassessment at the end of NAC showed 23.0% of the patients with a complete response, 33.0% of the patients with a partial response, and 37.0% of the patients with a stable disease, according to RECIST criteria. No progression with treatment has been reported. Pathological analysis of the cystectomy specimens found residual disease (≥pT2) in 83.5% of patients treated with prior surgery versus 44.8% of patients treated with NAC (P <0.01). The rate of pN+ patients was comparable in the two groups (37.1% versus 33.3%, P =0.746). Twenty-three patients (18.1%) received adjuvant chemotherapy, including four in the NAC group. After a median follow-up of 21.6 months [9.9–35], 50 patients (39.3%) had progressed, and 34 (26.7%) had died. Figure 3 represents the survival curves between the two groups. NAC was associated with a decreased risk of progression (HR=0.44, [0.21; 0.94], P =0.03), with no statistically significant benefit on overall survival (HR=0.52, [0.22; 1.27], P =0.14).


Figure 3
Figure 3. 

Progression-free and overall survival curves with and without NAC.





Discussion


Despite a proven benefit in overall survival, with a high level of evidence [5], the use of neoadjuvant chemotherapy in real life remains limited in patients with localized MIBC. In this single-center series, less than a quarter of the patients started neoadjuvant chemotherapy, and, of these, another quarter did not receive full treatment due to toxicity reasons. European and American data show a comparable underuse of NAC, with approximately 20% of patients treated [6, 8, 9]. There are several reasons for this situation. First, 57% of the patients in this study had contraindications to the administration of cisplatin-based chemotherapy. In the literature, approximately half of patients are not eligible for treatment due to renal failure (GFR<60mL/min), poor general condition (ECOG-PS≥2), heart failure, neuropathy or hypoacusis (grade≥2) [10, 11]. These patients could theoretically receive treatment with carboplatin, but several trials in a metastatic situation have shown poorer efficacy compared to cisplatin, and its benefit at the localized stage has never been demonstrated [12]. Therefore, in a non-metastatic situation, the use of carboplatin-based chemotherapy remains limited to patients with locally advanced disease or cN+ as part of primary chemotherapy. There is currently a therapeutic gap for patients who are ineligible for cisplatin in a neoadjuvant situation.


Although the patients treated with NAC were significantly younger, with better general health and better renal function, more than a quarter of these patients were unable to complete treatment due to chemotherapy-related toxicities, including half of severe complications (grade 3–4). Other studies have found similar complication rates [13, 14, 15]. This high rate of complications may explain the reluctance to administer NAC if the complications lead to a deterioration of the general condition, preventing surgery. For 23% of patients, analysis of the file did not find an objective contraindication to the NAC. Therefore, it seems that some patients, who could in theory benefit from this treatment, ultimately do not have access to it. Similar rates are found in the literature [13] and could be explained in part by the underestimation of symptomatic patients with persistent hematuria or disabling lower system symptoms. These symptomatic forms leading to an initial cystectomy represent between four and 20% of cases in the literature [16]. However, there is also surgical reluctance to use NAC, particularly because of the risk of toxicity. One of the concerns raised is the delay in carrying out curative treatment by cystectomy, especially in patients who do not respond to chemotherapy. A delay between MIBC diagnosis and cystectomy greater than 12 weeks is associated with decreased survival in the absence of NAC [17, 18]. Nevertheless, a more recent study has shown that, subject to initiating NAC within seven weeks of diagnosis, the time to surgery had no effect on survival, including in patients who did not respond to NAC [19]. However, when the time between the end of chemotherapy and cystectomy exceeds twelve weeks, the risk of lymph node invasion is significantly increased [20]. In our series, the median time from the end of chemotherapy to surgery was 5.3 weeks. A greater risk of perioperative complications after NAC has also been suggested. In our study, no significant difference was found concerning the operating duration, rate of surgical complications or length of hospitalization. Blood loss was even lower in the group treated with NAC. Other retrospective studies have also shown that NAC does not induce additional surgical morbidity [21]. However, not all patients benefit from NAC, and the pathological response rate≤pT1 was 55% in our series. In the literature, the response rate after NAC is between 20 and 40% and is associated with a significant improvement in survival [22, 23]. Several biomarkers of response to chemotherapy are currently being evaluated, including certain mutations [24, 25, 26] or molecular subtypes [27], to select the patients most able to respond and avoid treating non-responsive patients. The impossibility of a systematic analysis of molecular subtypes in routine is currently a major limitation preventing the selection of patients according to this criterion. Due to the lack of centralized reading of slides in our center, it is not possible to know for all patients the hypothetical presence of histological variants with poor prognosis. This could also be an additional argument in favor of the administration of neoadjuvant chemotherapy; however, there is currently no formal argument in the literature in favor of this hypothesis.


The future of neoadjuvant therapy in MIBC may hinge on immunotherapy. Clinical trials evaluating checkpoint inhibitors alone or in combination with chemotherapy are underway. The results of 2 phase II studies with atezolizumab (ABACUS) or pembrolizumab (PURE-01) conducted in 95 and 50 patients with localized MIBC show a pathological response rate of 31 and 42%, respectively, with a more favorable safety profile [28, 29]. The development of biomarkers could make possible in the future to better select patients who are candidates for neoadjuvant therapy while avoiding potential adverse effects in non-responder patients. If their efficacy is confirmed in the phase III setting, immunological checkpoint inhibitors could make it possible to treat a larger number of patients.


This single-center retrospective study has several limitations. First, the workforce remains relatively small. Second, the causes of NAC refusal were not found for all patients. This led us to believe that there was still reluctance to administer NAC. This hypothesis is also suggested by the absence of an increase in the rate of patients treated with NAC in our center in recent years, contrary to the data in the literature on the subject [30]. Finally, the patients included in this study underwent radical cystectomy for MIBC. Among these patients, a number had cN+disease, and chemotherapy was more like induction chemotherapy than neoadjuvant chemotherapy. However, the results of this real-life study are consistent with data in the literature and suggest the underuse of NAC.


Conclusion


NAC is recommended in the treatment of localized MIBC before cystectomy, in the absence of contraindication, as it provides a benefit in survival. However, our real-life data show that a minority of patients, namely, those who are younger and in better condition, benefit. In addition, almost a quarter of patients have not received treatment in the absence of an objective contraindication, suggesting that there is still a significant reluctance to use NAC. These results confirm the need to sensitize the urological community to the oncological benefits of NAC in the absence of contraindications.


Disclosure of interest


The authors declare that they have no competing interest.




Table 1 - Characteristics of the population.
  Total
n =127 
No NAC
n =97 
NAC
n =30 
P   n  
Sex        0.765  127 
Men  109 (85.8%)  84 (86.6%)  25 (83.3%)     
Women  18 (14.2%)  13 (13.4%)  5 (16.7%)     
Age  73.0 [66.0; 79.5]  75.0 [68.0; 81.0]  66.5 [62.2; 73.0]  <0.001  127 
Preoperatory GFR  64.0 [47.0; 76.0]  56.0 [43.0; 70.0]  78.5 [67.2; 99.5]  <0.001  127 
ECOG/WHO-PS        0.012  127 
88 (69.3%)  61 (62.9%)  27 (90.0%)     
31 (24.4%)  28 (28.9%)  3 (10.0%)     
8 (6.0%)  8 (8.3%)  0 (0.0%)     
cT        0.196  126 
118 (93.7%)  89 (91.8%)  29 (100%)     
8 (6.4%)  8 (8.3%)  0 (0.0%)     
cN        <0.001  127 
107 (84.3%)  90 (92.8%)  17 (56.7%)     
20 (15.7%)  7 (7.2%)  13 (43.3%)     
Delay diagnosis/treatment (days)  56.0 [37.5; 80.0]  58.0 [41.0; 83.0]  43.0 [33.0; 73.0]  0.135  127 
Delay diagnosis/surgery (days)  70.0 [48.0; 112.0]  58.0 [41.0; 83.0]  126 [110.0; 154.0]  <0.001  127 
Delay diagnosis/NAC (days)  37.4 [32.0; 46.0]  NA  37.4 [32.0; 46.0]    127 
Urinary diversion        0.012  127 
None  2 (1.6%)  2 (2.1%)  0 (0.0%)     
Bricker  75 (59.1%)  64 (66.0%)  11 (36.7%)     
Neobladder  46 (36.2%)  29 (29.9%)  17 (56.7%)     
Ureterostomy  4 (3.2%)  2 (2.1%)  2 (6.7%)     
Surgical complications        1.000  127 
No  65 (51.2%)  50 (51.5%)  15 (50.0%)     
Yes  62 (48.8%)  47 (48.5%)  15 (50.0%)     
GFR delta (mL/min)  2.00 [−10.5; 14.0]  5.00 [−6.0; 16.0]  −17.00 [−29.0; −0.3]  <0.001  127 
pT        <0.001  126 
≤pT1  32 (25.4%)  16 (16.5%)  16 (55.2%)     
≥pT2  94 (74.6%)  81 (83.5%)  13 (44.8%)     
pN        0.746  127 
pN0  73 (57.5%)  54 (55.7%)  19 (63.3%)     
pN+  46 (36.2%)  36 (37.1%)  10 (33.3%)     
pNx  8 (6.3%)  7 (7.2%)  1 (3.3%)     
Follow-up (months)  21.6 [9.9; 35.1]  18.3 [7.5; 34.2]  29.1 [19.3; 37.5]  0.015  127 
Progression        0.157  127 
No  77 (60.6%)  55 (56.7%)  22 (73.3%)     
Yes  50 (39.4%)  42 (43.3%)  8 (26.7%)     
Death        0.470  127 
No  93 (73.2%)  69 (71.1%)  24 (80.0%)     
Yes  34 (26.8%)  28 (28.9%)  6 (20.0%)     





Table 2 - Refusal of NAC: causes.
Causes  n (%) 
Age>75 years-old  42 (43.3%) 
GFR<60mL/min  45 (46.4%) 
ECOG/WHO-PS> 7 (7.2%) 
Patient's medical history  12 (12.4%) 
Patient refusal  2 (2.1%) 
Unspecified  23 (23.7%) 





Table 3 - Uni- and multi-variate analysis of predictive factors of NAC administration.
  Univariate 
Multivariate 
  OR [EIQ95%]  P   OR [EIQ95%]  P  
Sex         
Men  Reference    Reference   
Women  1.31 [0.38–3.91]  0.649  1.18 [0.23–5.18]  0.827 
Age  0.92 [0.87–0.96]  <0.001  0.96 [0.91–1.02]  0.279 
Preoperatory GFR  1.05 [1.03–1.08]  <0.001  1.04 [1.02–1.07]  0.001 
cN         
cN0  Reference    Reference   
cN+  9.49 [3.36–29.2]  <0.001  8.09 [2.34–31.5]  0.001 




References



Cumberbatch M.G.K., Jubber I., Black P.C., Esperto F., Figueroa J.D., Kamat A.M., et al. Epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018 Eur Urol 2018 ;  74 (6) : 784-795 [cross-ref]
Chamie K., Litwin M.S., Bassett J.C., Daskivich T.J., Lai J., Hanley J.M., et al. Recurrence of high-risk bladder cancer: a population-based analysis Cancer 2013 ;  119 (17) : 3219-3227 [cross-ref]
Rouprêt M., Neuzillet Y., Pignot G., Compérat E., Audenet F., Houédé N., et al. Recommandations françaises du Comité de cancérologie de l’AFU — actualisation 2018–2020 : tumeurs de la vessie Progres En Urol J Assoc Francaise Urol Soc Francaise Urol 2018 ;  28 (12S) : S46-S78 [inter-ref]
Grossman H.B., Natale R.B., Tangen C.M., Speights V.O., Vogelzang N.J., Trump D.L., et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer N Engl J Med 2003 ;  349 (9) : 859-866 [cross-ref]
Yin M., Joshi M., Meijer R.P., Glantz M., Holder S., Harvey H.A., et al. Neoadjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and two-step meta-analysis Oncologist 2016 ;  21 (6) : 708-715 [cross-ref]
Reardon Z.D., Patel S.G., Zaid H.B., Stimson C.J., Resnick M.J., Keegan K.A., et al. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides Eur Urol 2015 ;  67 (1) : 165-170 [cross-ref]
Dindo D., Demartines N., Clavien P.-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey Ann Surg 2004 ;  240 (2) : 205-213 [cross-ref]
Burger M., Mulders P., Witjes W. Use of neoadjuvant chemotherapy for muscle-invasive bladder cancer is low among major European centres: results of a feasibility questionnaire Eur Urol 2012 ;  61 (5) : 1070-1071 [cross-ref]
Carvalho F.L., Zeymo A., Egan J., Kelly C.H., Zheng C., Lynch J.H., et al. Determinants of neoadjuvant chemotherapy use in muscle-invasive bladder cancer Investig Clin Urol 2020 ;  61 (4) : 390-396 [cross-ref]
Thompson R.H., Boorjian S.A., Kim S.P., Cheville J.C., Thapa P., Tarrel R., et al. Eligibility for neoadjuvant/adjuvant cisplatin-based chemotherapy among radical cystectomy patients BJU Int 2014 ;  113 (5b) : E17-E21
Galsky M.D., Hahn N.M., Rosenberg J., Sonpavde G., Hutson T., Oh W.K., et al. Treatment of patients with metastatic urothelial cancer “unfit” for Cisplatin-based chemotherapy J Clin Oncol 2011 ;  29 (17) : 2432-2438 [cross-ref]
Galsky M.D., Chen G.J., Oh W.K., Bellmunt J., Roth B.J., Petrioli R., et al. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma Ann Oncol 2012 ;  23 (2) : 406-410 [cross-ref]
Raj G.V., Karavadia S., Schlomer B., Arriaga Y., Lotan Y., Sagalowsky A., et al. Contemporary use of perioperative cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer Cancer 2011 ;  117 (2) : 276-282 [cross-ref]
Meyer V., Flechon A., Tartas S., Fassi-Fehri H., Ruffion A., Martin X., et al. Impact de la chimiothérapie néoadjuvante sur la prise en charge des tumeurs de vessie infiltrant le muscle Progres En Urol J Assoc Francaise Urol Soc Francaise Urol 2015 ;  25 (2) : 83-89 [cross-ref]
Nayan M., Bhindi B., Yu J.L., Mamdani M., Fleshner N.E., Hermanns T., et al. The initiation of a multidisciplinary bladder cancer clinic and the uptake of neoadjuvant chemotherapy: a time-series analysis Can Urol Assoc J J Assoc Urol Can 2016 ;  10 (1–2) : 25-30 [cross-ref]
Dobbs R.W., Hugar L.A., Revenig L.M., Al-Qassab S., Petros J.A., Ritenour C.W., et al. Incidence and clinical characteristics of lower urinary tract symptoms as a presenting symptom for patients with newly diagnosed bladder cancer Int Braz J Urol 2014 ;  40 (2) : 198-203 [cross-ref]
Gore J.L., Lai J., Setodji C.M., Litwin M.S., Saigal C.S., Urologic Diseases in America Project Mortality increases when radical cystectomy is delayed more than 12 weeks: results from a surveillance, epidemiology, and end results-medicare analysis Cancer 2009 ;  115 (5) : 988-996 [cross-ref]
Kulkarni G.S., Urbach D.R., Austin P.C., Fleshner N.E., Laupacis A. Longer wait times increase overall mortality in patients with bladder cancer J Urol 2009 ;  182 (4) : 1318-1324 [cross-ref]
Audenet F., Sfakianos J.P., Waingankar N., Ruel N.H., Galsky M.D., Yuh B.E., et al. A delay≥8 weeks to neoadjuvant chemotherapy before radical cystectomy increases the risk of upstaging Urol Oncol 2019 ;  37 (2) : 116-122 [cross-ref]
Mmeje C.O., Benson C.R., Nogueras-González G.M., Jayaratna I.S., Gao J., Siefker-Radtke A.O., et al. Determining the optimal time for radical cystectomy after neoadjuvant chemotherapy BJU Int 2018 ;  122 (1) : 98
Salminen A.P., Koskinen I., Perez I.M., Hurme S., Murtola T.J., Vaarala M.H., et al. Neoadjuvant chemotherapy does not increase the morbidity of radical cystectomy: a 10-year retrospective nationwide study Eur Urol Oncol 2018 ;  1 (6) : 525-530 [cross-ref]
Lavery H.J., Stensland K.D., Niegisch G., Albers P., Droller M.J. Pathological T0 following radical cystectomy with or without neoadjuvant chemotherapy: a useful surrogate J Urol 2014 ;  191 (4) : 898-906 [cross-ref]
Zargar H., Espiritu P.N., Fairey A.S., Mertens L.S., Dinney C.P., Mir M.C., et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer Eur Urol 2015 ;  67 (2) : 241-249 [cross-ref]
Van Allen E.M., Mouw K.W., Kim P., Iyer G., Wagle N., Al-Ahmadie H., et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma Cancer Discov 2014 ;  4 (10) : 1140-1153 [cross-ref]
Plimack E.R., Dunbrack R.L., Brennan T.A., Andrake M.D., Zhou Y., Serebriiskii I.G., et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer Eur Urol 2015 ;  68 (6) : 959-967 [cross-ref]
Groenendijk F.H., de Jong J., Fransen van de Putte E.E., Michaut M., Schlicker A., Peters D., et al. ERBB2 mutations characterize a subgroup of muscle-invasive bladder cancers with excellent response to neoadjuvant chemotherapy Eur Urol 2016 ;  69 (3) : 384-388 [cross-ref]
Seiler R., Ashab H.A.D., Erho N., van Rhijn B.W.G., Winters B., Douglas J., et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy Eur Urol 2017 ;  72 (4) : 544-554 [cross-ref]
Necchi A., Anichini A., Raggi D., Briganti A., Massa S., Lucianò R., et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase ii study J Clin Oncol 2018 ;  36 (34) : 3353-3360 [cross-ref]
Powles T., Kockx M., Rodriguez-Vida A., Duran I., Crabb S.J., Van Der Heijden M.S., et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial Nat Med 2019 ;  25 (11) : 1706-1714 [cross-ref]
Krabbe L.-M., Westerman M.E., Margulis V., Raj G.V., Sagalowsky A.I., Courtney K., et al. Changing trends in utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer Can J Urol 2015 ;  22 (4) : 7865-7875






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