Adjuvant chemotherapy versus observation after radical cystectomy in patients with node-positive bladder cancer.
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ABSTRACT:
SUBMITTER: Pak S
PROVIDER: S-EPMC6549178 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
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Adjuvant chemotherapy versus observation after radical cystectomy in patients with node-positive bladder cancer.
Pak Sahyun S You Dalsan D Jeong In Gab IG Song Cheryn C Lee Jae-Lyun JL Hong Bumsik B Hong Jun Hyuk JH Kim Choung-Soo CS Ahn Hanjong H
Scientific reports 20190605 1
This retrospective study compared adjuvant chemotherapy (AC) versus observation after radical cystectomy (RC) in patients with node-positive bladder cancer (pN+). Outcomes were reviewed in patients with pTanyN1-3M0 bladder cancer who underwent RC with or without AC between 1995 and 2017. Baseline characteristics between the two groups were controlled with inverse probability of treatment weighting (IPTW)-adjusted analyses. Of 281 enrolled patients, the 3-year IPTW-adjusted rates of overall survi ...[more]
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Project description:Background: Benefits of adjuvant chemotherapy (AC) and extent of pelvic lymph node dissection (PLND) in radical cystectomy (RC) are debated. Results from randomized trials are still expected. Objective: To analyze the effects of AC and PLND in two academic centers with opposite policies regarding their use. Methods: 581 bladder cancer patients who underwent RC without neoadjuvant chemotherapy, from Toronto (University Health Network), Canada, and Turku University Hospital, Finland were included. Disease specific survival (DSS) and failure patterns were assessed. Results: Centers differed in PLND rate (93% and 36% in Toronto and Turku respectively, p?< ?0.001), PLND extent (?10 removed nodes, 58% vs. 8%, p?< ?0.001) and AC rate (21% vs. 2%, p?< ?0.001). Survival between centers among pT?1 or pT4 patients was similar. pT3 patients in Toronto had an improved 10 year DSS (43% vs. 22%, p?=?0.025). Distant failures were less common after AC (HR 0.56, 95% ?CI 0.33-0.98, p?< ?0.042). In node positive (N+) patients, mortality was significantly higher in Turku (HR 2.19, 95% ?CI 1.44-3.34, p?< ?0.001) and lower in patients receiving AC (HR 0.60, 95% ?CI 0.37-0.99, p?=?0.044). 41% DSS at 10 years was observed in N+?Toronto patients. Limitations included the non-randomized retrospective design and absence of propensity score analysis. Conclusion: Combining AC and PLND to RC is associated with improved survival in pT3 and N+?patients. PLND did not affect survival independently but helps in selecting patients for AC. Our data adds to the growing body of evidence supporting the usefulness of AC in addition to PLND in high risk patients operated by cystectomy.
| S-EPMC4927915 | biostudies-other
Project description:ImportanceDespite existing evidence of a benefit associated with cisplatin-based adjuvant chemotherapy (AC) after radical cystectomy (RC) for chemotherapy-naive patients with pT3/T4 and/or pN+ urothelial carcinoma of the bladder (UCB), to our knowledge, no studies have addressed the effectiveness of AC in those who received neoadjuvant chemotherapy (NAC) before surgery.ObjectiveTo assess the comparative effectiveness of AC vs observation for patients with pT3/T4 and/or pN+ UCB previously treated with NAC and RC.Design, setting, and participantsThis observational cohort study used the National Cancer Data Base (January 1, 2006, through December 31, 2012) to identify individuals who received NAC and RC followed by AC or observation for pT3/T4 and/or pN+ UCB.Main outcomes and measuresAfter multiple imputation was used to handle missing data, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier and Cox proportional hazards regression analyses were performed with a 6-month conditional landmark to compare overall survival (OS) among patients who received NAC and RC followed by AC vs observation. In addition, exploratory analyses were conducted to examine the heterogeneity of the treatment effect according to age (continuous), sex (female vs male), Charlson comorbidity index (?1 vs 0), pT/N stage (pT3/T4N0 vs pTanyN+), and surgical margin status (positive vs negative) by testing interaction terms within the IPTW-adjusted Cox proportional hazards regression model.ResultsOf the 788 patients with pT3/T4 and/or pN+ UCB (mean [SD] age, 65.3 [9.4] years; 603 [76.5%] male and 185 [23.5%] female), 184 (23.4%) received NAC and RC followed by AC and 604 (76.6%) received NAC and RC followed by observation. The 6-month conditional landmark, IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for NAC and RC followed by AC (29.9 months; interquartile range, 15.1-85.4 months) vs NAC and RC followed by observation (24.2 months; interquartile range, 12.9-58.9 months) (P?=?.046). The 5-year IPTW-adjusted rates of OS were 36.8% for NAC and RC followed by AC vs 24.7% for NAC and RC followed by observation. In the IPTW-adjusted Cox proportional hazards regression analysis, NAC and RC followed by AC was associated with a significant OS benefit (hazard ratio, 0.78; 95% CI, 0.61-0.99; P?=?.046). Interaction term analyses indicated that the OS benefit of NAC and RC followed by AC decreased significantly with age (hazard ratio, 0.97; 95% CI, 0.95-0.99; P?=?.02), whereas no significant interaction was observed with sex (P?=?.82), Charlson comorbidity index (P?=?.51), pT/N stage (P?=?.95), and surgical margin status (P?=?.29).Conclusions and relevanceThis study found that AC after NAC and RC may be associated with an OS benefit for patients with pT3/T4 and/or pN+ UCB. The present findings should be considered as preliminary evidence to conduct a randomized clinical trial to address this association.
| S-EPMC5838707 | biostudies-literature
Project description:Introduction and objectiveMuscle invasive bladder cancer with extravesical extension is an aggressive disease entity that requires multimodal therapy. The benefits of adjuvant chemotherapy (AC) in patients with a positive soft-tissue surgical margin (STSM), however, are relatively unknown due to exclusion of this population in randomized controlled trials of AC. We sought to define survival benefits in this patient population through our institutional bladder cancer database.MethodsRetrospective review of all patients undergoing radical cystectomy for urothelial carcinoma of the bladder from 2004-2020 with ≥pT3b disease irrespective of neoadjuvant chemotherapy (NAC) use was conducted. Progression-free survival (PFS) and overall survival (OS) estimates were obtained using the Kaplan-Meier method with log-rank test, and the Cox-proportional hazards model was used to identify predictors of improved PFS and OS. AC was defined by any chemotherapy use within 90 days of cystectomy, regardless of STSM status.Results476 patients with pT3b disease or worse were identified. Median follow-up was 12.3 months. An amount of 21% of patients were treated with AC. An amount of 24% of patients had positive STSM. Median OS for patients with positive STSM was 8.4 months [95% CI 7-11.5] and 18.3 months [95% CI 15.6-20.8] (p < 0.001) for patients with negative STSM. In the overall cohort, positive STSM (HR 1.93, 95% CI 1.45-2.57, p < 0.001), AC use (HR 0.68, 95% CI 0.51-0.90, p = 0.007), and pN1-3 disease (HR 1.47, 95% CI 1.16-1.87, p = 0.002) were independent predictors of OS when adjusted for performance status, pT-stage, and neoadjuvant chemotherapy use. In patients with positive STSM, median survival was seven months [95% CI 5.2-8.4] without AC, compared to 16.2 months [95% CI 11.5-52.5] with AC (p = 0.0038). For patients with negative STSM, median survival was 17.4 months [95% CI 14-20.1] without AC compared to 22.3 months [95% CI 17.2-36.9] with AC (p = 0.23). In patients with positive STSM, AC use was the only factor associated with an OS benefit with a HR of 0.41 (95% CI 0.21-0.78, p = 0.007). In patients with negative STSM, pT4 and pN1-3 disease were the only factors associated with worse overall survival with a HR of 1.32 (95% CI 1.00-1.74, p = 0.050) and 1.97 (95% CI 1.49-2.60, p < 0.001), respectively.ConclusionsAdministration of adjuvant chemotherapy is of particular benefit in patients with positive STSM following radical cystectomy for gross extravesical disease. Positive STSM may be a representative of "early metastatic" or micrometastatic disease.
| S-EPMC10046994 | biostudies-literature
Project description:OBJECT:To elucidate the impact of adjuvant chemotherapy (ACH) on survival in patients with urothelial carcinoma of the bladder (UCB) diagnosed with pT3 disease (perivesical tissue invasion). METHODS:We reviewed the clinical data of 424 patients who underwent radical cystectomy (RC) with bilateral pelvic lymphadenectomy for UCB in our institution between 1991 and 2012. None of the patients received neoadjuvant chemotherapy. Of all patients, 101 (23.8%) were diagnosed with pT3 disease: pT3a in 43 patients and pT3b in 58 patients. The Kaplan-Meier method with the log-rank test was used to estimate and compare overall survival (OS) and cancer-specific survival (CSS) between groups. Multivariate Cox proportional hazard models were used to identify predictors of OS and CSS. RESULTS:Five-year OS (48.5% vs. 45.6%) and CSS (56.1% vs. 56.2%) were similar in the pT3a and pT3b groups (p = 0.658 and 0.840, respectively). In all pT3 patients, ACH administration was an independent predictor for OS (p = 0.018), but not CSS (p = 0.623) on multivariate analyses. On multivariate analysis according to the pT3 sub-stage, ACH was significantly associated with improved OS (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.17-0.72, p = 0.004) and CSS (HR 0.33; 95% CI 0.10-0.85, p = 0.022) in only the pT3b group. CONCLUSION:Our data suggest that in pT3b disease, characterized by macroscopic perivesical tissue invasion, patients may obtain an OS benefit from the administration of ACH. Thus, our findings provide evidence for establishing appropriate indications for ACH in muscle invasive UCB.
| S-EPMC4504111 | biostudies-literature
Project description:Importance:Locoregional failure for patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity and mortality. Adjuvant radiotherapy (RT) can decrease locoregional failure but has not been studied in the chemotherapy era. Objective:To investigate if adjuvant sequential RT plus chemotherapy can improve locoregional recurrence-free survival (LRFS) compared with adjuvant chemotherapy alone. Design, Setting, and Participants:A randomized phase 3 trial was opened to compare adjuvant RT vs sequential chemotherapy plus RT after RC for LABC, but a third arm was added later as a randomized phase 2 trial to compare chemotherapy plus RT vs adjuvant chemotherapy alone, an emerging standard. The intent-to-treat phase 2 trial reported herein enrolled patients from December 2002 to July 2008. Data were analyzed from August 3, 2015, to January 6, 2016. Routine follow-up and surveillance pelvic computed tomographic (CT) scans every 6 months during the first 2 years were performed. The setting was an academic center. Patients with bladder cancer 70 years or younger having 1 or more risk factors (≥pT3b, grade 3, or positive nodes) with negative margins after radical cystectomy plus pelvic lymph node dissection were eligible. Patients had Eastern Cooperative Oncology Group performance status of 0 to 2, no evidence of distant metastases on CT scan of the abdomen and pelvis or on chest imaging, and adequate renal, hepatic, and hematologic function. Ninety-one percent (109 of 120) had ≥ pT3 disease. Interventions:Chemotherapy plus RT included 2 cycles of gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15) and cisplatin (70 mg/m2 intravenously on day 2) before and after RT to 4500 cGy in 150 cGy twice-daily fractions over 3 weeks using 3-dimensional conformal techniques. Chemotherapy alone included 4 cycles of gemcitabine and cisplatin. Main Outcome and Measure:Locoregional recurrence-free survival. Results:The chemotherapy plus RT arm accrued 75 patients, and the chemotherapy-alone arm accrued 45 patients, with a weighted randomization to speed accrual. Fifty-three percent (64 of 120) had urothelial carcinoma, and 46.7% (56 of 120) had squamous cell carcinoma or other. The arms were balanced except for age (median, 52 vs 55 years; P = .04) and tumor size (mean, 4.9 vs 5.8 cm; P < .01), both favoring chemotherapy plus RT. Two-year outcomes and overall adjusted hazard ratios (HRs) for chemotherapy plus RT vs chemotherapy alone were 96% vs 69% (HR, 0.08; 95% CI, 0.02-0.39; P < .01) for LRFS, 68% vs 56% (HR, 0.53; 95% CI, 0.27-1.06; P = .07) for disease-free survival, and 71% vs 60% (HR, 0.61; 95% CI, 0.33-1.11; P = .11) for overall survival (OS). Five patients (7%) had RT-associated late grade 3 gastrointestinal tract adverse effects in the chemotherapy plus RT arm. Conclusions and Relevance:Adjuvant chemotherapy plus RT was reasonably well tolerated and was associated with significant improvements in LRFS and marginal improvements in disease-free survival vs chemotherapy alone in LABC. The addition of adjuvant RT should be considered for LABC. This regimen warrants further study in phase 3 trials. Trial Registration:clinicaltrials.gov Identifier: NCT01734798.
| S-EPMC5833621 | biostudies-literature
Project description:ObjectivesTo compare perioperative and oncologic survival outcomes between laparoscopic radical cystectomy and open radical cystectomy.MethodsA total of 607 patients underwent open radical cystectomy (n = 412) or laparoscopic radical cystectomy (n = 195) at a single academic institution from January 2006 to April 2017. Their medical records were retrospectively analyzed. One-to-one propensity score matching was carried out to reduce selection bias. Estimated blood loss and complications were compared. Overall survival, cancer-specific survival and progression-free survival estimates for all patients and patients with locally advanced bladder cancer were analyzed using the Kaplan-Meier method.ResultsEither before or after matching, the laparoscopic radical cystectomy group had less estimated blood loss (P < 0.001 and P < 0.001) and fewer complications (P < 0.001 and P = 0.008). There was no difference in the overall survival (P = 0.216 and P = 0.961) and progression-free survival (P = 0.826 and P = 0.462) for all the patients having either laparoscopic radical cystectomy or open radical cystectomy. However, the 5-year progression-free survival of open radical cystectomy was higher than that of laparoscopic radical cystectomy (P = 0.019 and P = 0.021) for patients with locally advanced bladder cancer.ConclusionsLaparoscopic radical cystectomy is superior to open radical cystectomy in terms of perioperative outcomes, and similar to open radical cystectomy in terms of oncologic outcomes for patients with early stage bladder cancer. However, for patients with locally advanced bladder cancer, laparoscopic radical cystectomy seems to be associated with shorter progression-free survival than open radical cystectomy.
| S-EPMC9291606 | biostudies-literature
Project description:BackgroundNeo-adjuvant chemotherapy followed by radical cystectomy with extended pelvic lymph node dissection is considered to be the treatment of choice for patients with muscle invasive bladder cancer (MIBC). Despite this aggressive treatment the outcome is poor and ultimately, 30% of the patients with ≥pT3 tumors develop a pelvic recurrence. We hypothesize that postoperative adjuvant external beam radiotherapy (EBRT) might prevent local and lymph node recurrence and improve disease free- and overall survival as loco-regional recurrence is linked to the development of distant metastasis.MethodsWe plan to perform a multicentric prospective phase two study including 76 patients. Eligible patients are patients with MIBC, treated with radical cystectomy and presenting with ≥1 of the following characteristics: Pathological (p)T3 stage + presence of lymphovascular invasion on pathological examination pT4 stage <10 lymph nodes removed positive lymph nodes positive surgical margins Patients will have a 18F-FDG PET-CT to rule out the presence of distant metastasis prior to EBRT. A median dose of 50 Gy in 25 fractions is prescribed to the pelvic lymph node regions with inclusion of the operative bladder bed in case of a positive surgical margin. Patients with suspected lymph nodes on PET- CT can still be included in the trial, but a simultaneous integrated boost to 74Gy to the positive lymph nodes will be delivered. Blood and urine samples will be collected on day-1 and last day of EBRT for evaluation of biomarkers. The primary endpoint is evaluation of acute ≥Grade 3 intestinal or grade 4 urinary toxicity, in case of a neo-bladder reconstruction, within 12 weeks after EBRT. Secondary endpoints are: assessment of QOL, late RTOG toxicity, local control, disease free survival and overall survival. Biomarkers in urine and blood will be correlated with secondary survival endpoints.DiscussionThis is a prospective phase 2 trial re-assessing the feasibility of adjuvant radiotherapy in high-risk MIBC.Trial registrationThe Ethics committee of the Ghent University Hospital (EC2014/0630) approved this study on 31/07/2014. Trial registration on Clinicaltrials.gov ( NCT02397434 ) on November 19, 2014.
| S-EPMC5414216 | biostudies-literature
Project description:Assessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit. Gene expression of CD3Z, CD8A and CXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival. The gene expression signature of CXCL9, CD3Z and CD8A correlates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44-0.74; TCGA: ρ-range: 0.56-0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with 'inflamed high' tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort). The gene expression signature of CD3Z, CD8A and CXCL9 can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy.
| S-EPMC7253053 | biostudies-literature
Project description:Bladder cancer (BCa) is the tenth most commonly diagnosed malignant cancer worldwide. Although adjuvant chemotherapy following radical cystectomy is a common therapy for muscle invasive bladder cancer patients, no applicable biomarkers exist to predict which patients will benefit from chemotherapy. In this study, we examined three immune cell markers, the chemokine CC motif ligand 2 (CCL2), the pan macrophage marker cluster of differentiation 68 (CD68) and the M2 macrophage marker cluster of differentiation 163 (CD163), using immunohistochemistry to determine their predictive value for the chemotherapy response in different nodal stage (pN0 vs. pN1 + 2) and tumor stage subgroups (pT2 vs. pT3 + 4). The prognosis was studied in terms of the overall survival (OS), disease-specific survival (DSS), and recurrence-free-survival (RFS) in 168 muscle invasive BCa patients. Chemotherapy was associated with a poorer prognosis in patients with a higher expression of the immune markers CCL2 (RFS), CD68 (DSS and RFS), and CD163 (DSS and RFS) in the N0 group and with poorer survival in patients with a higher expression of the immune markers CCL2 (OS, DSS, and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS, DSS, and RFS) in the pT2 group when compared with treatments without chemotherapy. In contrast, chemotherapy was associated with a better prognosis in patients with a low expression of the immune markers CCL2 (DSS and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS) in the N1 + 2 group. In addition, chemotherapy was associated with improved survival in patients with a low expression of the immune marker CD68 (OS and DSS) and there was a trend for a better prognosis in patients with a low expression of CD163 (OS) in the pT3 + 4 group compared to patients not treated with chemotherapy. Interestingly, CD68 appeared to be the most applicable immune marker to stratify patients by the outcome of chemotherapy in the nodal stage and tumor stage groups. Overall, we suggest that, in addition to the clinical factors of tumor stage and nodal stage, it is also meaningful to consider the abundance of immune cells, such as macrophages, to better predict the response to chemotherapy for BCa patients after radical treatment.
| S-EPMC7829767 | biostudies-literature
Project description:BACKGROUND:Bladder cancer is a complex disease associated with high morbidity and mortality. Management of bladder cancer before radical cystectomy continues to be controversial. We compared the long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy (IAC) versus no IAC (NIAC) before radical cystectomy (RC) for bladder cancer. METHODS:We performed a retrospective review of patients who underwent either one-shot IAC or NIAC before RC between October 2006 and November 2015. A propensity-score matching (1:3) was performed based on key characters. The Kaplan-Meier method was utilized to estimate survival probabilities, and the log-rank test was used to compare survival outcomes between different groups. A multivariable Cox proportional hazard model was used to estimate survival outcomes. RESULTS:Twenty-six patients were treated using IAC before RC, and 123 NIAC patients also underwent RC. After matching, there was no significant difference between groups in baseline characteristics, perioperative variables, complication outcomes or tumor characteristics. Compared with clinical tumor stages, pathological tumor stages demonstrated a significant decrease (P?=?0.002) in the IAC group. There was no significant difference in overall survival (OS, p?=?0.354) or cancer-specific survival (CSS, p?=?0.439) between the groups. Among all patients, BMI significantly affected OS (p?=?0.004), and positive lymph nodes (PLN) significantly affected both OS (p<0.001) and CSS (p?=?0.010). CONCLUSIONS:One-shot neoadjuvant IAC before RC shows safety and tolerability and provides a significant advantage in pathological downstaging but not in OS or CSS. Further study of neoadjuvant combination therapeutic strategies with RC is needed.
| S-EPMC6858971 | biostudies-literature