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1.
World J Urol ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31463561

RESUMO

PURPOSE: To improve patient selection for neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in bladder cancer patients (BCa). METHODS: Retrospective evaluation of 1057 patients with cT2-4N0M0 BCa treated with RC and pelvic lymph node dissection between 1990 and 2018 at 3 referral centers. Adverse pathologic features (APF) were defined as pT3-pT4/pN + disease at RC. A regression tree model (CART) was used to assess preoperative risk group classes. A multivariable logistic regression (MVA) was performed to identify predictors of APF at RC. RESULTS: Median age was 70 years and most of the patients were men (83%). Of the 1057 patients included in our study, 688 (65%) had APF. CART analysis was able to stratify patients into 3 risk groups: low (cT2 and single disease, odds ratio [OR] 0.62), intermediate (cT2 and multiple disease, OR 1.08), and high (cT3-cT4, OR 1.28). On MVA APF were associated with variant histology (odds ratio [OR] 3.97, 95% confidence interval [CI] 1.46-10.83, p = 0.007), multifocality at TUR (OR 2.56, CI 1.27-5.17, p = 0.09), completeness of resection (OR 0.47, CI 0.23-0.96, p = 0.04) and clinical extravesical disease (OR 3.42, CI 1.63-7.14, p = 0.001). CONCLUSION: We defined three pre-operative risk classes. Our results indicate that patients with a cT3-T4 disease are those who might benefit more from NAC whereas those with T2 single disease should be those to whom NAC probably shouldn't be proposed. Given the high rate of understaging in BCa patients, NAC can be proposed in selected cases of cT2/multifocal disease.

2.
Eur Urol ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31303258

RESUMO

The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2-4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p=0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3-4 or pN1 disease who received AC (75% vs 54%; p<0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p=0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%. Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation.

3.
BJU Int ; 2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31055865

RESUMO

OBJECTIVES: To compare trends in the use of robot-assisted radical cystectomy (RARC) and changes over time in peri-operative outcomes in selected North American and European centres. MATERIALS AND METHODS: We conducted a retrospective evaluation of 2401 patients treated with open radical cystectomy (ORC) or RARC for bladder cancer at 12 centres in North America and Europe between 2006 and 2018. We used the Kruskal-Wallis and chi-squared test to evaluate differences between continuous and categorical variables. RESULTS: Overall, 49.5% of patients underwent RARC and 51.5% ORC. RARC became the most commonly performed procedure in contemporary patients, with an increase from 29% in 2006-2008 to 54% in 2015-2018 (P < 0.001). In the North American centres the use of RARC was higher than that of ORC from 2006, and remained stable over time, whereas in the European centres its use increased exponentially from 2% to 50%. In both groups patients who underwent RARC had less advanced T stages (P < 0.001), lower American Society of Anesthesiologists scores (P < 0.05), lower blood loss (P = 0.001) and shorter length of hospital stay (P < 0.05). No differences were found in early complications. Early readmission and re-operation rates were worse for patients treated with RARC in the European centres; however, when contemporary patients only were considered, the statistical significance was lost. CONCLUSION: The present study shows that the use of RARC has constantly increased since its introduction, overtaking ORC in the most contemporary series. While RARC was more frequently performed than ORC since its introduction in the North American centres and its use remained substantially stable over time, its use increased exponentially in the European centres. The different trends in use of RARC/ORC and changes over time in peri-operative outcomes between the North American and European centres can be attributed to the earlier introduction and spread of RARC in the former compared with the latter.

4.
BJU Int ; 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31144770

RESUMO

OBJECTIVE: To examine the incidence and time trends of secondary bladder cancer (BCa) and rectal cancer (RCa) after brachytherapy (BT) relative to radical prostatectomy (RP). MATERIALS AND METHODS: Within the Surveillance, Epidemiology and End Results (SEER) database (1988-2015), we identified patients with localized PCa as an only or first primary cancer, who underwent BT or RP. Cumulative incidence plots and multivariable competing-risks regression (CRR) models were used. Sensitivity analyses focused on patients' age and year of diagnosis intervals and tested the effect of an unmeasured confounder. RESULTS: Of 318 058 patients with localized prostate cancer (PCa), 55 566 (18.4%) underwent BT. After propensity score-matching, 20-year secondary BCa incidence was 6.0% in patients who had undergone BT vs 2.4% in those who had undergone RP (P < 0.001) and the respective 20-year secondary RCa incidence was 1.1% vs 0.5% (P < 0.001). In multivariable CRR models, BT predicted higher secondary BCa (hazard ratio [HR] 1.58; P < 0.001) and RCa rates (HR 1.59; P < 0.001) vs RP. Sensitivity analyses replicated the same results after stratification according to age and showed HRs of decreasing magnitude for historical, intermediate and contemporary years of diagnosis. An unmeasured confounder with an HR of 2 would render the effect of BT statistically insignificant if it affected patients in the RP group with a ratio of 2 relative to those in the BT group. Finally, temporal trends showed a decrease of secondary 5-year BCa and RCa rates.> CONCLUSIONS: Brachytherapy predominantly increases the risk of secondary BCa and, to a lesser extent, that of RCa. Follow-up of such patients is therefore required. It is encouraging that both secondary BCa, and RCa rates, in particular, have recently decreased, RCa.

5.
J Geriatr Oncol ; 10(4): 623-631, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31010691

RESUMO

BACKGROUND: Analyzing the relationship between perioperative outcomes and age in urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC) in a continuous fashion may provide detailed information on the increased risk of complications in older patients, even after accounting for different comorbidity profiles. Given the limited data available in the literature, we tested these relationships within a large scale, population-based database. MATERIALS AND METHODS: Within the NIS database (2003-2015), we identified patients who underwent RC for UCB. Multivariable logistic regression (MLoR) and Poisson regression (MPR) models were used after adjustment for clustering and stratification for comorbidity profiles. RESULTS: Overall, 20,144 patients underwent RC with a median age of 70 years (interquartile range: 62-77). In MLoR models, continuously coded age represented an independent predictor of overall (odds ratio [OR]: 1.008, 95%-confidence interval [CI]: 1.005-1.012), cardiac (OR: 1.042, 95%-CI: 1.035-1.049), vascular (OR: 1.024, 95%-CI: 1.014-1.034), respiratory (OR: 1.016, 95%-CI 1.009-1.022), miscellaneous medical (OR: 1.013, 95%-CI: 1.009-1.017), infectious (OR: 1.012, 95%-CI 1.004-1.019), transfusions (OR: 1.011, 95%-CI 1.007-1.015) and bowel obstruction (OR: 1.009, 95%-CI 1.004-1.013) complications, and in-hospital mortality (OR: 1.057, 95%-CI 1.039-1.075). Conversely, patients age did not predict intraoperative (p = 0.7), genitourinary (p = 0.9), operative wound (p = 0.2) and miscellaneous surgical complications (p = 0.1). In MPR models, patients age predicted longer LOS (relative risk [RR]: 1.002, 95%-CI 1.001-1.003). Finally, a decreasing effect of age was observed in patients low vs high comorbidity burden for cardiac, respiratory and overall complications. CONCLUSIONS: Most of early postoperative RC complications are related to patients age, but its impact varies according to comorbidity profile. Further studies are needed to validate our findings that may be then considered for individual counselling and informed consent, as well as for health expenditure planning.

6.
Eur Urol Oncol ; 2(2): 196-197, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31017096

RESUMO

In the hands of experienced surgeons at referral centers, robotic surgery with an intracorporeal urinary diversion has the potential to provide better perioperative outcomes without affecting cancer control when compared to open surgery for radical cystectomy.

7.
World J Urol ; 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911811

RESUMO

PURPOSE: To evaluate the role of a complete transurethral resection of bladder tumors (c-TURBT) on oncological outcomes after radical cystectomy (RC) and its relationship with adverse pathological features. METHODS: We retrospectively analyzed data of 727 patients treated with RC and bilateral pelvic lymph node dissection at three tertiary referral centers. Possible c-TURBT was reported by the treating surgeon. Multivariable Cox regression analyses were used to assess the relationship of c-TURBT and survival outcomes after surgery in 1:1 propensity score-matched cohort adjusted for age and gender. Moreover, multivariable logistic regression (MVA) was built to predict the relationship between c-TURBT and pT3-T4 stages at RC, lymph node invasion (LNI) and positive soft tissue surgical margin (STSM). RESULTS: A total of 433 (60%) patients received a c-TURBT. 3.0% of patients with a c-TURBT achieved a pT0-pTa-pTis status vs. 2.0% of patients with incomplete TURBT. At multivariable Cox regression analyses, c-TURBT was not associated with survival outcomes. At MVA, incompleteness of TURBT was significantly associated with a pT3-T4 stage [odds ratio (OR) 8.04, 95% confidence interval (CI) 2.33-27.67, p = 0.001]. No significant association was found between c-TURBT, LNI and STSM. CONCLUSION: We found a low rate of achievement of pT0 stage at RC. An incomplete TURBT before RC represented a predictor of pT3-T4 stages, but no effect of a c-TURBT was shown on survival outcomes. Given the current inadequacy of clinical staging strategies with more than 50% of extravesical disease being under-staged, our results could improve patients selection for NAC, driving the decision-making in doubtful cases.

8.
Clin Genitourin Cancer ; 17(3): e541-e548, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30850337

RESUMO

INTRODUCTION: Patients with bladder cancer treated with radical cystectomy (RC) have heterogeneous results in term of cancer-specific (CSM) and other cause mortality (OCM). Our aim is to assess the impact of age on cause of death after RC. PATIENTS AND METHODS: We retrospectively analyzed the data of 1222 patients treated with RC and bilateral pelvic lymph node dissection owing to nonmetastatic bladder cancer between 1990 and 2013. Patients were stratified according to age (< 59 vs. 60-69 vs. 70-79 vs. ≥ 80 years), tumor T stage at RC (pT0-T2 vs. pT3-T4), and tumor N stage at RC (pN+ vs. pN0). Competing-risks survival analyses were used to estimate CSM and OCM rates. RESULTS: With a median follow up of 6 years, 92 (7.5%) and 385 (31.5%) OCM and CSM were recorded. The 5-year CSM and OCM rates were 40% and 8.8%, respectively. After stratification according to disease stage and patient age, CSM emerged as the main cause of mortality in all patient subgroups. The 5-year OCM was 4.6%, 4.8%, 11%, and 32% for patients aged < 60 years versus 60 to 69 years versus 70 to 79 years versus ≥ 80 years, respectively. The 5-years CSM was 34%, 45%, 35%, and 56% for patients aged < 60 years versus 60 to 69 years versus 70 to 79 years versus ≥ 80 years, respectively. Similar findings were observed stratifying the population according to pathologic T and N stage. CONCLUSION: CSM is the preponderant cause of death for all the patients, regardless of age or stage. In this regard, RC also seems to be a reasonable approach for octogenarians.

9.
Ann Surg Oncol ; 26(6): 1942-1949, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919224

RESUMO

PURPOSE: The Deyo adaptation of the Charlson comorbidity index (DaCCI), which relies on 17 comorbid condition groupings defined with 200 ICD-9-CM diagnostic codes, lacks specificity in the context of radical cystectomy (RC) for bladder cancer (BCa). We attempted to develop a new comorbidity assessment tool based on individual comorbid conditions and/or BCa manifestations for specific prediction of perioperative mortality after RC. METHODS: We relied on 7076 T1-T4 nonmetastatic BCa patients treated with RC between 2000 and 2009 in the SEER-Medicare linked database. Within the development cohort (n = 6076), simulated annealing (SA) was used to identify (1) individual comorbid conditions, (2) individual BCa manifestations, and (3) the combination of both, that satisfy the criteria of maximal accuracy and parsimony for prediction of 90-day mortality after RC, after adjusting for several confounders. The accuracy of the newly identified groups of individual comorbid conditions and/or BCa manifestations and of the original DaCCI was tested in a 1000-patient external validation cohort. RESULTS: The combination of six individual comorbid conditions and two individual BCa disease manifestations (type II diabetes without complications, anemia, chronic obstructive pulmonary disease, congestive heart failure, aortocoronary bypass, cardiomegaly, urinary tract infection, and hydronephrosis), and seven individual comorbid conditions (type II diabetes without complications, anemia, chronic obstructive pulmonary disease, congestive heart failure, aortocoronary bypass, osteoarthrosis, and cardiomegaly) respectively showed 71.1 and 70.2% accuracy versus 68.0% for the original DaCCI. CONCLUSIONS: These new approaches are specific to contemporary RC patients and represent simpler methods compared with the original DaCCI, without any compromise in accuracy.


Assuntos
Comorbidade , Cistectomia/mortalidade , Modelos Estatísticos , Assistência Perioperatória/mortalidade , Medição de Risco/métodos , Neoplasias da Bexiga Urinária/mortalidade , Idoso , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Programa de SEER , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia
10.
Eur J Surg Oncol ; 45(7): 1253-1259, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30755341

RESUMO

BACKGROUND: Locally advanced muscle-invasive bladder cancer (MIBC) patients who are candidates for radical cystectomy (RC) should receive perioperative chemotherapy (CHT). However, the adherence to CHT guidelines is low. Thus, we tested contemporary CHT use rates and associated cancer-specific mortality (CSM) and overall mortality (OM) rates. MATERIALS AND METHODS: Within the SEER database (2004-2015), we identified pT3N0/+ MIBC patients, who underwent RC, with or without perioperative CHT. Estimated annual percentage changes (EAPCs) analyses were used. After inverse probability of treatment weighting (IPTW), Kaplan-Meier (KM) analyses and Cox regression models (CRMs) tested the association of CHT on survival in the overall population (n = 3817), as well as after stratification according to stage, gender and age. Landmark analyses tested for immortal time bias. RESULTS: Overall, 44.3% of patients received CHT. Between 2004 and 2015, CHT administration rates increased from 32.1% to 55.6% (EAPC: +6.0%; p < 0.001). In CRMs, CHT was associated with lower CSM (HR 0.73, CI 0.65-0.81) and OM (HR 0.69, CI 0.62-0.76). In sensitivity analyses, CHT was also associated with lower CSM and OM in N0 patients (CSM: HR 0.76, 95% CI 0.65-0.88; OM: HR 0.69, 95% CI 0.60-0.79) and in N+ patients (CSM: HR 0.69, 95% CI 0.59-0.80; OM: HR 0.67, 95% CI 0.58-0.77), as well as according to gender and age. Landmark analyses confirmed the above results. CONCLUSIONS: Perioperative CHT was associated with better survival and its rate of use increased in locally-advanced MIBC RC patients. The latter confirm one large observational study and several small prospective studies.

11.
J Urol ; 202(1): 108-113, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30747873

RESUMO

PURPOSE: Improved cancer control with increasing surgical experience (the learning curve) has been demonstrated for open and laparoscopic prostatectomy. We assessed the relationship between surgical experience and oncologic outcomes of robot-assisted radical prostatectomy. MATERIALS AND METHODS: We analyzed the records of 1,827 patients in whom prostate cancer was treated with robot-assisted radical prostatectomy. Surgical experience was coded as the total number of robotic prostatectomies performed by the surgeon before the patient operation. We evaluated the relationship of prior surgeon experience to the probability of positive margins and biochemical recurrence in regression models adjusting for stage, grade and prostate specific antigen. RESULTS: After adjusting for case mix, greater surgeon experience was associated with a lower probability of positive surgical margins (p = 0.035). The risk of positive margins decreased from 16.7% to 9.6% in patients treated by a surgeon with 10 and 250 prior procedures, respectively (risk difference 7.1%, 95% CI 1.7-12.2). In patients with nonorgan confined disease the predicted probability of positive margins was 38.4% in those treated by surgeons with 10 prior operations and 24.9% in those treated by surgeons with 250 prior operations (absolute risk reduction 13.5%, 95% CI -3.4-22.5). The relationship between surgical experience and the risk of biochemical recurrence after surgery was not significant (p = 0.8). CONCLUSIONS: Specific techniques used by experienced surgeons which are associated with improved margin rates need further research. The impact of experience on cancer control after robotic prostatectomy differed from that in the prior literature on open and laparoscopic radical prostatectomy, and should be investigated in larger multi-institutional studies.


Assuntos
Laparoscopia/estatística & dados numéricos , Curva de Aprendizado , Margens de Excisão , Recidiva Local de Neoplasia/epidemiologia , Prostatectomia/estatística & dados numéricos , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos/estatística & dados numéricos , Competência Clínica/estatística & dados numéricos , Humanos , Laparoscopia/educação , Laparoscopia/métodos , Masculino , Recidiva Local de Neoplasia/prevenção & controle , Próstata/patologia , Próstata/cirurgia , Prostatectomia/educação , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Procedimentos Cirúrgicos Robóticos/educação , Procedimentos Cirúrgicos Robóticos/métodos , Cirurgiões/educação , Cirurgiões/estatística & dados numéricos , Resultado do Tratamento
12.
Urol Int ; 102(3): 269-276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695782

RESUMO

INTRODUCTION: According to TNM staging, pathological T4ab are comprehensive of the invasion of prostate, seminal vesicles, uterus or vagina and pelvic or abdominal wall. However, few data are available on the perioperative and oncological outcomes of specific organ invasion. MATERIALS AND METHODS: A total of 917 consecutive bladder cancer (BCa) patients treated with radical cystectomy (RC) at a single institution between 1990 and 2015 were studies. Cox regression analyses were used to stratify pT4ab according to the site of invasion and survival. RESULTS: Overall, 176 (19.2%) and 40 (4.4%) patients harbored pT4a or pT4b disease. Specifically, 84 (9.2%) patients reported prostate and/or SVI invasion, 62 (6.8%) prostate only, 16 (1.7%) uterus, 14 (1.5%) vaginal, 24 (2.6%) pelvic wall, and 16 (1.7%) abdominal wall invasion. The median follow-up in pT4 patients was 48 months. The 1-year cancer-specific mortality (CSM) rates were 71, 65, 24, 50, 50, and 72%, for vaginal, uterus, prostate only, prostate and/or seminal vesicles, pelvic wall, and abdominal wall invasions, respectively. At multivariable Cox regression, the invasion of prostate only (hazard ratio [HR] 3.53), prostate and/or SVI (HR 4.98), uterus (HR 7.16), vagina (HR 6.12), pelvic (HR 11.81), abdominal (8.36) were associated with adverse CSM. CONCLUSIONS: Our study described the differences in survival related to invasion site in pT4 patients, confirming poor survival expectancies in this subgroup. Patients with prostate invasion only seem to be associated with better survival than those affected by concomitant invasion of seminal vesicles. Uterus and vaginal invasions were associated with poor survival outcomes. Patients Summary: In this study, we looked at the outcome of locally advanced invasive BCa (stage pT4) in patients treated with RC at a tertiary referral hospital. We analyzed the differences in survival related to the specific organ invasion. We confirmed poor survival in this subgroup of patients. Only patients who had prostate invasion only seem to have a better survival.

13.
Clin Genitourin Cancer ; 17(2): 105-113.e2, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30527745

RESUMO

BACKGROUND: Radical cystectomy (RC) may occasionally be performed in individuals with metastatic urothelial carcinoma of the bladder (mUCB). However, the role of lymph node dissection (LND) for such cases is unknown. Thus, we tested the effect of RC on cancer-specific mortality (CSM) and overall mortality in mUCB patients and the effect of LND and its extent on CSM. PATIENTS AND METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2013), we identified patients with mUCB who underwent RC with or without LND or non-RC management. Kaplan-Meier analyses and multivariable Cox regression models (CRMs) were used, after propensity score matching. The number of removed nodes best predicting CSM was identified using cubic splines and then was tested in multivariable CRMs. RESULTS: Of 2314 patients, 319 (13.8%) underwent RC. After 2:1 propensity score matching, CSM-free survival was 14 versus 8 months (P < .001), and overall mortality-free survival was 12 versus 7 months (P < .001) for, respectively, RC and non-RC patients. In multivariable CRMs, lower CSM (hazard ratio = 0.48; P < .001) and lower overall mortality (hazard ratio = 0.49; P < .001) rates were recorded in RC patients. LND status did not affect CSM-free survival (13 vs. 10 months; P = .1). Cubic splines-derived cutoff of ≥ 13 number of removed nodes showed better CSM-free survival (20 vs. 11 months; P = .02) and reduced CSM in CRMs (hazard ratio = 0.67; P = .02). CONCLUSION: Our study validates the survival benefit of RC in mUCB and highlights the importance of more extensive LND. These findings may corroborate the hypothesis of potential cytoreductive effect of surgery in the context of metastatic disease.

14.
Cancer Epidemiol ; 58: 83-88, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30528834

RESUMO

BACKGROUND: Patients with organ confined muscle-invasive bladder cancer (MIBC) who are candidates for radical cystectomy (RC) should receive neoadjuvant chemotherapy (CHT). However, the most contemporary CHT use rates indicate low adherence to these guidelines. We tested contemporary neoadjuvant CHT rates and associated cancer-specific mortality (CSM) and overall mortality (OM) in pT2N0 MIBC patients treated with RC. MATERIALS AND METHODS: Within the SEER database (2004-2015), we identified patients with pT2N0 MIBC patients who underwent RC. CHT administration rates were evaluated using estimated annual percentage changes (EAPCs) analyses. After inverse probability of treatment weighting (IPTW), Kaplan-Meier (KM) analyses and Cox regression models (CRMs) were used to test the effect of CHT vs no CHT on survival. Landmark analyses tested for immortal time bias. RESULTS: Of 3978 RC patients, 38.2% of patients received CHT. Between 2004 and 2015, CHT rates increased from 15.9% to 66.2% (EAPC: +14.2%; p < 0.001). IPTW-adjusted KM showed 10-year CSM-free survival rates of 78.9% for CHT vs 76.7% for no CHT patients (p = 0.6). Similarly, IPTW-adjusted KM showed 10-year OM-free survival rates of 54.6% for CHT vs 57.9% for no CHT patients (p = 0.8). In IPTW-adjusted MCRMs, CHT was not significantly associated with lower CSM (HR 0.97, CI 0.82-1.14; p = 0.7) or OM (HR 1.02, CI 0.90-1.16; p = 0.7). Virtually the same CSM and OM rates were recorded after landmark analyses. CONCLUSIONS: CHT use in pT2N0 MIBC RC patients sharply increased over the study span. However, neoadjuvant CHT was not associated with better survival in this patient group.

15.
J Clin Oncol ; : JCO1801148, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30343614

RESUMO

PURPOSE: To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used. PATIENTS AND METHODS: In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay. RESULTS: Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pT<2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of those with CPS < 10% (n = 15). A significant nonlinear association between tumor mutation burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several genes in pretherapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune resistance were observed in residual tumors. CONCLUSION: Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1-positive or high-TMB tumors.

16.
Artigo em Inglês | MEDLINE | ID: mdl-30292628

RESUMO

BACKGROUND: Limited information is available about the pattern of relapse after perioperative chemotherapy with radical cystectomy (RC) vs. RC alone in muscle-invasive bladder cancer. PATIENTS AND METHODS: Data from 1082 patients of the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium database, treated from February 1990 to December 2013 at 27 centers in the United States, Europe, Israel, and Canada, were collected. Locoregional relapse was defined as any pelvic lymph node or soft tissue-only recurrences. Cumulative incidence methods were used to estimate time to locoregional relapse (TTRL). Cox regression analyses were performed and a nomogram for 12-month locoregional relapse-free survival (RFS) was developed. The nomogram was applied to an external data set (n = 1021). RESULTS: A total of 517 patients (47.8%) developed a relapse: 177 (16.4%) exclusive locoregional relapse. In multivariable analyses, perioperative chemotherapy was associated with longer TTRL (P < .001). Other factors were nonurothelial histology (P = .013), pT-stage (P < .001), and surgical margins (P < .001). The concordance index of the model was 0.681 (95% bootstrapped confidence interval, 0.666-0.716). Risk group categories were obtained according to nomogram tertiles. Despite, overall, observed locoregional RFS in the validation cohort exceeding predicted results, for high-risk patients (80 points or less, lowest nomogram tertile) observed 12-month RFS was similar between development and validation cohorts (60.1% and 66.6%). The study is limited by its retrospective nature. CONCLUSION: In the largest study, to our knowledge, that analyzed locoregional recurrences after RC, we propose a risk prediction tool for exclusive locoregional failures that might be suitable for clinical studies. Patients best suited for adjuvant radiotherapy might be those within the lowest nomogram tertile. Prospective trials are needed to validate findings.

18.
Dalton Trans ; 47(25): 8268-8282, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29892758

RESUMO

Multi-action cisplatin-based mono- (1) and di-clofibric acid (2) Pt(iv) "combo" derivatives were synthesized via both traditional and microwave assisted procedures. The two complexes offered very good performances (IC50 values in a nanomolar range) on a panel of human tumor cell lines, including the highly chemoresistant malignant pleural mesothelioma ones. Moreover, both 1 and 2 bypass the cisplatin resistance. Indeed, cisplatin and clofibric acid, the metabolites of the Pt(iv) → Pt(ii) intracellular reduction, proved to act synergistically. The adjuvant action of clofibric acid relies on the activation of peroxisome proliferator-activated receptor α (PPARα) that, in turn, decreases the level of Hypoxia-Inducible Factor-1α. Both compounds induced extensive apoptosis in tumor cells, also via oxidative stress. Finally, 2 exhibited excellent performances also under the hypoxic conditions typical of solid tumors, where cisplatin is less effective.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/análogos & derivados , Cisplatino/farmacologia , Ácido Clofíbrico/química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Concentração Inibidora 50 , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/química
19.
Urol Oncol ; 36(6): 307.e9-307.e14, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29602638

RESUMO

BACKGROUND: Pelvic lymph node dissection (PLND) has a diagnostic and therapeutic role during radical cystectomy in bladder cancer patients. However, at the time, no prospective data supports the value of extended PLND in improving survival expectances. We sought to describe incidence and location of node metastases in patients treated with extended and superextended PLND. METHODS: We evaluated 653 contemporary patients with clinically nonmetastatic high risk nonmuscle invasive or muscle-invasive bladder cancer treated with radical cystectomy and extended or superextended PLND without neoadjuvant chemotherapy at a single tertiary referral center between 1990 and 2013. Limited PLND is defined as the removal of obturator and internal iliac nodes. Standard included also the external iliac nodes. Extended includes also common and presacral nodes. Finally, superextended PLND includes all the nodes removed along the inferior mesenteric artery. We evaluated incidence of pathologically node metastases. Logistic regression analyses evaluate preoperative and pathologic characteristics to the risk of harboring node metastases in the extended and superextended template. RESULTS: Overall, 191 (29.3%) patients were found with pathologically node confirmed metastases. Of these, 56 (29.3%) patients were found with a single node metastasis, while 135 (70.7%) had multiple node metastases. The vast majority of patients were found with node metastases standard template (n = 172, 26.3%), on the other hand 30 (4.6%) and 21 (3.2%) patients had node metastases in extended and superextended templates, respectively. However, of these only 2 patients were found without concomitant lymph node metastases in the limited or standard templates. On multivariable analyses, cN+ status (odds ratio = 4.40, P<0.001) and cT3-4 vs. cT1-2 (odds ratio = 2.25, P<0.001) were associated with an increased risk of harboring node metastases in the extended or superextended template. CONCLUSIONS: We found that the majority of patients harbored node disease in the limited or standard node dissection pattern. On the other hand, only a minority of patient were found with a disease in extended or superextended template without harboring a concomitant node disease in the limited pattern.


Assuntos
Cistectomia , Linfonodos/cirurgia , Neoplasias Pélvicas/secundário , Neoplasias Pélvicas/cirurgia , Neoplasias da Bexiga Urinária/patologia , Idoso , Feminino , Seguimentos , Humanos , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/cirurgia
20.
Eur Urol Focus ; 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29366856

RESUMO

BACKGROUND: Aborted radical prostatectomy (aRP) in lymph node (LN) metastatic (pN1) prostate cancer (PCa) patients showed worse survival in European patients. Contemporary rates of aRP are unknown in North America. OBJECTIVE: To examine the rate of aRP and its effect on cancer-specific mortality (CSM) in contemporary North American patients. DESIGN, SETTING, AND PARTICIPANTS: Within the Surveillance Epidemiology and End Results database (2004-2014), we identified 3719 pN1 PCa patients. INTERVENTION: RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incidence proportion and median survival of LN metastatic PCa patients who underwent aRP versus completed RP (cRP). Cumulative incidence plots and competing-risks regression (CRR) models tested CSM and other-cause mortality rates according to aRP versus cRP. The effect of selected variables on CSM rate was graphically depicted using LOESS methodology. All analyses were repeated after propensity score matching. RESULTS AND LIMITATIONS: Between 2004 and 2014, the rate of aRP decreased from 20.4% to 5.6% (p<0.001). Ten-year CSM rates were significantly higher after aRP (38.9% vs 21.6%) versus cRP (p<0.001). In multivariable CRR models, aRP yielded higher CSM (hazard ratio [HR]: 1.99) than cRP. A higher 5-yr CSM rate was recorded after aRP through the entire range of baseline prostate-specific antigen (PSA) values and in patients with up to nine LN metastases. After propensity score matching, aRP resulted in overall higher CSM (HR: 1.72). Higher CSM was recorded after aRP for PSA values up to 50ng/ml and in patients with up to seven LN metastases. Results were limited by a selection bias that applies to aRP patients. CONCLUSIONS: Of contemporary North American patients, 5% are affected by aRP. It confers a significant survival disadvantage that applies to patients with baseline PSA values up to 50ng/ml and in those with up to seven LN metastases. PATIENT SUMMARY: Radical prostatectomy should not be aborted in pN1 prostate cancer individuals.

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